- Email: [email protected]
Fate determination of cerebral cortical GABAergic interneurons and their derivation from stem cells
Brain Research 1655 (2017) 277–282
Contents lists available at ScienceDirect
Brain Research journal homepage: www.elsevier.com/locate/brainres
Review
Fate determination of cerebral cortical GABAergic interneurons and their derivation from stem cells Erik M. DeBoer, Stewart A. Anderson n Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania, School of Medicine, 3615 Civic Center Blvd, ARC 517, Philadelphia, PA 19104-5127, USA
art ic l e i nf o
a b s t r a c t
Article history: Accepted 15 December 2015 Available online 23 December 2015
Cortical GABAergic interneurons modulate cortical excitation, and their dysfunction is implicated in a multitude of neuropsychiatric disorders including autism, schizophrenia and epilepsy. Consequently, the study of cortical interneuron development, and their derivation from stem cells for transplantation therapy, has garnered intense scientific interest. In this review, we discuss some of the molecular signals involved in cortical interneuron fate determination, and describe how this has informed the use of mouse and human embryonic stem cell biology in generating cortical interneurons in vitro. We highlight the tremendous progress that has been made recently using stem cells to derive cortical interneurons, as well as challenges that have arisen. This article is part of a Special Issue entitled SI:StemsCellsinPsychiatry. & 2016 Published by Elsevier B.V.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origins of cortical interneurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cortical interneuron fate determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. MGE derived interneurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Interneuron generation outside the MGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Generation of interneurons from pluripotent stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mouse embryonic stem cells (mESCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Human stem cells (hESCs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction GABAergic cortical interneurons, also called local circuit neurons (LCNs) can be segregated into at least three categories based on protein marker expression, morphology and electrophysiological characteristics (Ascoli et al., 2008; DeFelipe et al., 2013; Kawaguchi and Kubota, 1997; Rudy et al., 2011). The first group, parvalbuminpositive (PV) interneurons, are fast spiking, minimally accommodating, and can be subdivided morphologically into at least two n
Corresponding author. E-mail addresses: [email protected] (E.M. DeBoer), [email protected] (S.A. Anderson). http://dx.doi.org/10.1016/j.brainres.2015.12.031 0006-8993/& 2016 Published by Elsevier B.V.
277 278 278 278 278 279 279 279 281
groups: chandelier and basket cells. Basket cells innervate pyramidal neurons as well as other interneurons at the proximal dendritic segments and cell body (Kepecs and Fishell, 2014). PVpositive chandelier cells preferentially innervate the axon initial segment of pyramidal neurons (Somogyi, 1977). The second group of interneurons express the neuropeptide somatostatin (SST), tend to innervate the distal dendrite of pyramidal neurons and some interneurons, and fire action potentials in bursting or in accommodating patterns. The final, 5HT3aR-expressing interneuron subgroup is highly diverse in morphology, axon targeting and physiological characteristics (Miyoshi et al., 2010). Cortical interneurons serve to modulate the firing of glutamatergic projection neurons as well as other interneurons, such that disruption of interneuron
278
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
distribution and wiring is associated with neuropsychiatric disorders, including autism, schizophrenia and epilepsy (Marin, 2012).
2. Origins of cortical interneurons Cortical GABAergic interneurons are born in the subpallial (ventral) forebrain, in the ganglionic eminences (MGE; LGE and CGE) (Anderson et al., 1997b; Brunstrom et al., 1997; de Carlos et al., 1996; DeDiego et al., 1994; Hansen et al., 2013; Ma et al., 2013; Tamamaki et al., 1997). After cell cycle exit, they undergo a longer, non-radial migration into the developing cortical plate than excitatory cortical projection neurons, which originate in the dorsal telencephalon and migrate along radial glial fibers. It is unclear why cortical pyramidal neurons and interneurons have distinct origins; although cortical evolution may have followed a path of importation of GABAergic cells from the predominantly GABA-producing subpallium rather than evolving the capacity for pallial neuroepithelium to produce GABAergic in addition to glutamatergic neurons (Marin and Rubenstein, 2001).
3. Cortical interneuron fate determination 3.1. MGE derived interneurons The majority of cortical interneurons are SST or PV expressing (Gonchar et al., 2007; Tamamaki et al., 2003; Xu et al., 2010b), and originate from Nkx2.1-expressing progenitors in the MGE and in the preoptic region (Butt et al., 2005; Gelman et al., 2009; Xu et al., 2004, 2008). In the ventral forebrain, sonic Hedgehog (Shh) is required for development, including the induction of Nkx2.1. (Hebert and Fishell, 2008). Interestingly, after initial patterning is established, Shh remains necessary for the maintenance of Nkx2.1 expression in mitotic progenitors of the MGE but not in their post-mitotic progeny (Gulacsi and Anderson, 2006; Xu et al., 2010a, 2005). This Nkx2.1 maintenance role underlies a remarkable plasticity of MGE progenitors to generate different interneuron subgroups depending on conditions. For example, MGE progenitors in which Shh signaling is eliminated in vivo can switch fates from that of MGE-derived PV or SST expressing interneurons, to typically CGE-derived bipolar, calretinin-expressing interneurons (Xu et al., 2010a). Such plasticity has important implications for the derivation of cortical interneurons from pluripotent stem cells, as discussed below. Although in most of the developing neuraxis, Shh signaling occurs in a gradient of ventral-high, dorsal-low, in the MGE this signaling is more complex. The dorsal region of the MGE expresses multiple markers indicative of high levels of Shh signaling, including Patched-1 and Gli1, relative to more ventral MGE regions (Wonders et al., 2008). Cortical transplantations of progenitors from this dorsal region, particularly earlier in neurogenesis (i.e. before E14.5), are enriched for SST interneurons relative to those expressing PV (Flames et al., 2007; Wonders et al., 2008; Xu et al., 2010a). Correspondingly, experiments in both transgenic mice and in mouse stem cells indicate that while some Shh signaling is required to maintain Nkx2.1 expression and thus MGE interneuron fate, higher levels favor the generation of SST interneurons over those expressing PV (Tyson et al., 2015; Xu et al., 2010a). How this effect is mediated remains unclear, although the Shh signaling target gene Nkx6.2 is selectively expressed in the dorsal-most MGE, and its loss results in a modest reduction of SST-expressing interneurons (Sousa et al., 2009). In addition to Shh signaling (SST-specified at higher levels, PV specified at lower levels), location within the MGE (SST biased to originate from the dorsal MGE, PV biased to originate from more ventral MGE), and time (SST biased to originate earlier in neurogenesis
and to occupy deeper cortical layers, PV biased to originate later in neurogenesis and to occupy more superficial cortical layers), another factor has been shown to critically influence MGE-derived interneuron fate determination. The periventricular proliferative zone of the developing telencephalon contains two domains, defined histologically as the ventricular zone and subventricular zone (Committee, 1970), or defined in terms of proliferative populations in a variety of ways, including apical (i.e. along the ventricular surface) or basal (i.e. abventricular) (Caviness et al., 2009). In the developing striatum, neurogenesis from abventricular mitoses is extensive remarkably early, (Sheth and Bhide, 1997), and neurogenesis in the VZ versus SVZ appears to result in the generation of distinct compartments of striatal projection neurons (Anderson et al., 1997a). Loss of cyclin D2, which is expressed by abventricular progenitors in the MGE and throughout the telencephalon, results in a relatively selective reduction of cortical PV interneurons compared to the SST subgroup (Glickstein et al., 2007a; Glickstein et al., 2007b). In contrast, loss of CoupTf2 increases cyclin D2 in the dorsal MGE and results in excess production of PV interneurons (Lodato et al., 2011). Finally, a recent study using in vivo fate mapping and fate manipulation of MGE progenitors demonstrated that apical neurogenesis in the MGE is strongly biased to produce SST interneurons, whereas basal neurogenesis generates mainly PV interneurons (Petros et al., 2015). Since ventricular zone neurogenic divisions tend to be asymmetric (generating one neuron and one progenitor), and SVZ divisions tend to be symmetric (generating either two progenitors or two neurons)(Glickstein et al., 2009), these results suggest that the mode of division also has a critical influence on interneuron fate determination (Petros et al., 2015). Downstream of Nkx2.1 in the MGE, several factors have been identified that influence cortical interneuron fate determination. Nkx2.1 itself is maintained in GABAergic interneurons fated for the striatum, and is downregulated in those fated for the cerebral cortex (Nobrega-Pereira et al., 2008). This striatal-cortical interneuron fate decision is also critically influenced by the transcription factors Dlx1 and Dlx2, and their regulation of Zfhx1b (McKinsey et al., 2013). Around the time of cell cycle exit, Nkx2.1 directly activates Lhx6 (Du et al., 2008), which is maintained in most MGE-derived interneurons throughout their post-mitotic lives and is required for their normal migration and post-migratory maturation (Flandin et al., 2011; Fragkouli et al., 2009; Lavdas et al., 1999; Liodis et al., 2007; Zhao et al., 2008). Downstream of Lhx6, the transcription factor Sox6 is also required for normal PV and SST interneuron development (Azim et al., 2009; Batista-Brito et al., 2009), as is Satb1. (Close et al., 2012). While a large number of additional intrinsic and extrinsic factors have been identified that influence interneuron migration, maturation, and integration into cortical circuitry, this process has been reviewed recently and is outside the scope of this review (Kepecs and Fishell, 2014; Kessaris et al., 2014). 3.2. Interneuron generation outside the MGE Outside of the Nkx2.1-expressing proliferative domains of the MGE and preoptic area, other subcortical regions of the telencephalon produce the remaining portion of cortical LCNs, and recent findings demonstrate that most of these lineages can be traced through their expression of Prox1 (Rubin and Kessaris, 2013). Several subtypes of LCNs are generated from CGE progenitors, including subsets of those expressing neuropeptide Y (NPY), Reelin, and calretinin (Butt et al., 2005; Miyoshi et al., 2010). In addition, CGEgenerated LCN subgroups all express the serotonin receptor 5HT3aR (Tricoire et al., 2010), and VIP is a fairly selective marker for a subset of CGE derived, vertically oriented, bipolar interneurons (Miyoshi et al., 2010). A small proportion of cortical interneurons also appear to have their mitotic origin in the LGE (Anderson et al., 2001; Cai et al., 2013). Regarding fate determination of CGE-derived
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
interneurons, this diverse group has been studied less thoroughly than those from the MGE, but Gsx2, CoupTF2, and Prox1 all have been implicated in CGE interneuron fate determination (Kanatani et al., 2008; Lodato et al., 2011; Miyoshi et al., 2015; Xu et al., 2010a). In addition, Fgf15/19 signaling enhanced the generation of CGE-like over MGE-like cortical interneurons from mouse embryonic stem cells (Danjo et al., 2011).
4. Generation of interneurons from pluripotent stem cells 4.1. Mouse embryonic stem cells (mESCs) Aberrations in GABA signaling and interneuron function have been implicated in the etiology of a variety of neuropsychiatric illnesses, prompting efforts to treat such conditions using interneuronbased transplantation therapies, reviewed in (Southwell et al., 2014; Tyson and Anderson, 2014). Promising preclinical results using interneuron transplantation therapy for “interneuronopathies” have stimulated keen interest in generating cortical interneurons from a theoretically unlimited and potentially patient-derived source: stem cells. Early attempts to generate interneurons began using mouse embryonic stem cells (mESCs) over 10 years ago. These investigations sought to mimic the developmental environment of stem cells in order to influence mESC differentiation into neuronal subtypes (Ding and Schultz, 2004; Ding et al., 2003). A subsequent study made a major breakthrough in demonstrating that WNT inhibition enhanced the generation of Foxg1expressing telencephalic progenitors, with the later addition of Shh producing some Nkx2.1-expressing progenitors (Watanabe et al., 2005). Here, stem cells were initially differentiated as floating embryoid bodies, then landed to generate an adherent culture. However, this protocol was more efficient at generating Pax6þ (cortex-like) progenitors than it was at producing Nkx2.1positive (MGE-like) progenitors (roughly 75% vs 40% respectively), and although some cells maintained in culture eventually expressed GABA, it was not clear whether these were cortical interneurons versus other GABAergic populations. Building on this work, and benefiting from an approach to modify embryonic stem cells with modified bacterial artificial chromosomes that allow better tissue-selective expression of fluorescent reporter constructs (Tomishima et al., 2007), investigators generated Lhx6-GFP mESC line (Maroof et al., 2010). Although induction of Foxg1 (telencephalic), Nkx2.1 (MGE-like, as Nkx2.1 but not Foxg1 is also expressed in hypothalamus), and Lhx6 remained at less than 5%, the ability to isolate newly postmitotic, putatively GABAergic interneuron-fated cells by FACS allowed for definitive demonstration of their MGE-interneuron like fates after transplantation into neonatal mouse neocortex. Both PV and SSTexpressing cells with interneuron-like morphologies and the appropriate subgroup selective electrophysiologies were identified in cortical slices 30 days after transplantation. Danjo et al., using a Foxg1-reporter line to optimize the generation of telencephaliclike progenitors, also extended the basic approach in Watanabe (2005) to find that the signaling molecule Fgf8 enhanced the generation of MGE-like interneurons, whereas Fgf15/19 enhanced the generation of CGE-like interneurons (Danjo et al., 2011). Of note, Shh signaling inhibition by the Tgf-β agonist activin can also direct ventralized mESC differentiations to bipolar calretinin expressing, CGE-like interneurons (Cambray et al., 2012), a result remarkably consistent with the fate-switching effects of Shh inhibition in the MGE in vivo (Xu et al., 2010a). Subsequent studies used reporter-expressing mouse ESCs to study the regulation of interneuron fate. Viral infection of the Lhx6-GFP line with mCherry-tagged Dlx1/2 enhancer elements allowed for the identification of shifting enhancer activation
279
during the transition from Olig2 þ interneuron progenitor to Lhx6þ postmitotic interneuron (Chen et al., 2013). Another group used the Lhx6-GFP BAC and modification of a bicistronic tet-inducible element to demonstrate that forced induction of Nkx2.1 can enhance the generation of Lhx6þ interneurons in the absence of Shh signaling (Petros et al., 2013). A similar but more elegant approach to using mESCs in the study of the transcriptional regulation of interneuron fate involved forced expression of Nkx2.1 by the nestin promoter (expressed in neural progenitors), together with a bicistronic tet-inducible construct to drive two genes of interest and a Dlx5/6-GFP reporter of GABAergic fate (Au et al., 2013). This study was the first to enhance the derivation of MGEderived interneuron subgroups, increasing the generation of PVþ interneurons relative to those expressing SST by the induced expression of Nkx2.1, Dlx2, and Lmo3. A subsequent study that remodified the Lhx6-GFP mESC line with an Nkx2.1-mCherry reporter, also described significant enrichments of either SST or PVexpressing interneurons by modifications of Shh exposure, time in culture, and sorting for Nkx2.1-mCherry (in which case the cells are identified after transplantation by their subsequent expression of Lhx6-GFP) versus Lhx6-GFP (Tyson and Anderson 2014). In sum, studies of directed differentiation of mESCs to cortical interneuron-like cells are finding that recapitulation of normal development in vitro can result in the generation of apparently “real” interneurons. An important caveat to this statement is that characterization of mESC-derived interneurons to date has at best been at the levels of neurochemical expression and action potential discharge pattern following current injection, and not at the level of specificity of axonal or dendritic connectivity. It should also be noted that transplantation itself, rather than an intrinsic failing of the mESC-derived interneurons to accurately differentiate, could result in differences between in vivo and in vitroderived interneurons. Be that as it may, this system is now being used by multiple groups to study the regulation of interneuron fate determination. Although at the time of writing this review the authors are not aware of publications using mESC-derived interneurons in transplantation studies to treat disease models, at least one paper has demonstrated the feasibility of such a study (Maisano et al., 2012). Importantly, and bolstered by advances in generating cortical interneuron-like cells from mESCs, the generation of these cells from human stem cells is yielding promising results in the development of cell based therapies. 4.2. Human stem cells (hESCs) The generation of cortical interneuron-like cells from human pluripotent stem cells originally lagged behind that of mouse studies, owing mainly to the far slower pace of differentiation of human stem cells, their tendency to die after replating, and the lack of approaches for purifying interneuron progenitors or post-mitotic precursors from the mixed populations that occur with any protocol. While a group of studies demonstrated the capacity of human stem cells to generate rostral-forebrain (telencephalic-like) progenitors (Goulburn et al., 2012), three studies were particularly critical in moving the field forward. First, the group of Sasai found that addition of the Rho-associated kinase (ROCK) inhibitor, Y-27632, greatly reduces apoptosis at passaging (Watanabe et al., 2007). Second, it was demonstrated that, as occurs in vivo and in mouse ESC protocols, differential Shh and Wnt signaling agonism or antagonism can be used to drive telencephalon-enriched (Foxg1þ) hESC derived cultures into cortical-like (Pax6þ , Emx1þ) or MGElike (Nkx2.1þ) progenitor fields (Li et al., 2009). These cells also showed capacity to differentiate into glutamatergic or GABAergic neurons. Third, it was shown that, by dual inhibition of the TGF-β pathway with the peptide noggin (replaceable by the small molecule LDN) and the small molecule SB431542, during initial phase of
280
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
differentiation, it was possible to rapidly obtain neural progenitors (Chambers et al., 2009). Early inhibition of WNT signaling, following the lead initially demonstrated by the group of Sasai on mESCs (Watanabe et al., 2005), to the “dual-smad” approach has led to the relatively rapid, relatively uniform generation of telencephalon-like progenitors. These progenitors can then be dorsalized or ventralized into a variety of telencephalic subfields and differentiated into a variety of neuronal subgroups, including putative cortical interneurons (Kim et al., 2014; Maroof et al., 2013; Nicholas et al., 2013). Progress in optimizing protocols for the generation of cortical interneurons from human stem cells received a significant boost when the Elefanty/Stanley group used homologous recombination to create a hESC line expressing GFP from the NKX2.1 locus (Goulburn et al., 2011). Drawbacks of this line include its heterozygosity for NKX2.1, which is associated with a movement disorder (Breedveld et al., 2002; Krude et al., 2002), and its NIH non-registry background. There was also a tendency for tumor development, although one group cleverly obviated this problem by FACS for both NKX2.1-GFP and PSA-NCAM (Nicholas et al., 2013). In addition, NKX2.1 is downregulated by most cortical interneurons prior to their migration into the neocortex, in both mice and humans (Hansen et al., 2013; Ma et al., 2013; Marin et al., 2000). However, this downregulation occurs over a period of at least 6 months following transplantation of hESC-derived MGE-like cells into the neocortex of immune-suppressed mice, such that the line has been used to generate large numbers of neurons with migratory, morphological, synaptic, electrophysiological, and neurochemical features consistent with an immature interneuron fate (Maroof et al., 2013; Nicholas et al., 2013). While these studies are highly promising, they underscore two major challenges to the generation of cortical interneurons from human stem cells. First is the protracted maturation of the human cells following xenograft. Interestingly, maturation appears to occur more quickly when the
human interneuron precursors are cultured with a mixed layer of rodent cortical neurons and astrocytes (Maroof et al., 2013), than when cultured on astrocytes alone (Nicholas et al., 2013). This mixed co-culture system should be amenable to mechanistic studies of human interneuron synaptogenesis and initial electrophysiological maturation in vitro. Second, both studies found few cells that differentiated into PV-expressing interneurons, which is perhaps the most illness-related subclass (Inan et al., 2013; Lewis et al., 2012; Marin, 2012). This was suggested to be secondary to the delayed maturation of human interneurons, which is a reasonable idea given that PV expression by cortical interneurons in primates is minimal until after birth (Anderson et al., 1995; Letinic and Kostovic, 1998). A recent study, however, demonstrated with mESCs that it is also quite possible that the protocols being used favor SST or PV interneurons due to their relatively high level of Shh (Tyson et al., 2015). Evidence in mouse established PV interneurons are generated primarily from subventricular zone divisions of cyclin D2-expressing progenitors (Petros et al., 2015). This may provide additional insights that could be applied to strategies for enriching generation of PV interneurons from hESCs. Despite the challenges to generating efficient reagents and protocols for making cortical interneurons from hESCs, two recent studies have demonstrated the efficacy of these cells for treating seizures in a rodent model (Cunningham et al., 2014; Liu et al., 2013). As interneuron-based transplantation therapies are covered elsewhere in this issue, these studies will not be elaborated upon here. However, it should be evident that tremendous progress has been made in generating cortical interneuron-like cells from both mouse and human stem cells. We can expect to see a shift from studies that emphasize better ways to make such cells, to studies that use this system for the study of normal and pathological development, and for the treatment interneuron related disease (Fig. 1).
Fig. 1. Above: A table representing the small molecules, recombinant proteins and genetic expression of molecules used in recent literature for (top row) maintaining ESCs (middle row) inducing MGE-like ventral forebrain progenitors and (bottom row) neuronal differentiation. Below: A schematic of interneuron fate determination in vivo. PVpositive interneurons are preferentially born in the dorsal region of the MGE, where SST-positive interneurons are born from the ventral MGE. WNT and BMP signaling is higher in the developing dorsal forebrain, therefore inhibitors of these pathways are often employed in interneuron differentiation protocols to ventralize progenitors. While the SHH gradient is higher ventrally than dorsally in the developing forebrain, evidence suggests that this gradient is reversed within the MGE. The SHH-high, dorsal MGE gives rise to early-born SST-interneurons which migrate more often to deep layers of the developing cortex, whereas the SHH-poor ventral MGE more often produces later born, PV-positive interneurons which are enriched in superficial layers. FGF15/19 appear to inhibit rostral identity and favor CGE lineages by inhibiting FGF8. Reciprocally, FGF8 has been employed to rostralized ventral forebrain progenitors in both hESC and mESC protocols.
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
References Anderson, S.A., Classey, J.D., Conde, F., Lund, J.S., Lewis, D.A., 1995. Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience 67, 7–22. Anderson, S.A., Eisenstat, D.D., Shi, L., Rubenstein, J.L., 1997b. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278, 474–476. Anderson, S.A., Marin, O., Horn, C., Jennings, K., Rubenstein, J.L., 2001. Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128, 353–363. Anderson, S.A., Qiu, M., Bulfone, A., Eisenstat, D.D., Meneses, J., Pedersen, R., Rubenstein, J.L., 1997a. Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. Neuron 19, 27–37. Ascoli, G.A., Alonso-Nanclares, L., Anderson, S.A., Barrionuevo, G., Benavides-Piccione, R., Burkhalter, A., Buzsaki, G., Cauli, B., Defelipe, J., Fairen, A., et al., 2008. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568. Au, E., Ahmed, T., Karayannis, T., Biswas, S., Gan, L., Fishell, G., 2013. A modular gainof-function approach to generate cortical interneuron subtypes from ES cells. Neuron 80, 1145–1158. Azim, E., Jabaudon, D., Fame, R.M., Macklis, J.D., 2009. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nat. Neurosci. 12, 1238–1247. Batista-Brito, R., Rossignol, E., Hjerling-Leffler, J., Denaxa, M., Wegner, M., Lefebvre, V., Pachnis, V., Fishell, G., 2009. The cell-intrinsic requirement of Sox6 for cortical interneuron development. Neuron 63, 466–481. Breedveld, G.J., van Dongen, J.W., Danesino, C., Guala, A., Percy, A.K., Dure, L.S., Harper, P., Lazarou, L.P., van der Linde, H., Joosse, M., et al., 2002. Mutations in TITF-1 are associated with benign hereditary chorea. Hum. Mol. Genet. 11, 971–979. Brunstrom, J.E., Gray-Swain, M.R., Osborne, P.A., Pearlman, A.L., 1997. Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4. Neuron 18, 505–517. Butt, S.J., Fuccillo, M., Nery, S., Noctor, S., Kriegstein, A., Corbin, J.G., Fishell, G., 2005. The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron 48, 591–604. Cai, Y., Zhang, Q., Wang, C., Zhang, Y., Ma, T., Zhou, X., Tian, M., Rubenstein, J.L., Yang, Z., 2013. Nuclear receptor COUP-TFII-expressing neocortical interneurons are derived from the medial and lateral/caudal ganglionic eminence and define specific subsets of mature interneurons. J. Comp. Neurol. 521, 479–497. Cambray, S., Arber, C., Little, G., Dougalis, A.G., de Paola, V., Ungless, M.A., Li, M., Rodriguez, T.A., 2012. Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors. Nat. Commun. 3, 841. Caviness Jr., V.S., Nowakowski, R.S., Bhide, P.G., 2009. Neocortical neurogenesis: morphogenetic gradients and beyond. Trends Neurosci. 32, 443–450. Chambers, S.M., Fasano, C.A., Papapetrou, E.P., Tomishima, M., Sadelain, M., Studer, L., 2009. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280. Chen, Y.J., Vogt, D., Wang, Y., Visel, A., Silberberg, S.N., Nicholas, C.R., Danjo, T., Pollack, J.L., Pennacchio, L.A., Anderson, S., et al., 2013. Use of "MGE Enhancers" for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons. PLoS One 8, e61956. Close, J., Xu, H., Garcia, N.D.M., Batista-Brito, R., Rossignol, E., Rudy, B., Fishell, G., 2012. Satb1 is an activity-modulated transcription factor required for the terminal differentiation and connectivity of MGE-derived cortical interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 32, 17690–17705. Committee, B., 1970. Embryonic vertebrate central nervous system: revised termnology. Anat. Rec. 166, 257–261. Cunningham, M., Cho, J.H., Leung, A., Savvidis, G., Ahn, S., Moon, M., Lee, P.K., Han, J. J., Azimi, N., Kim, K.S., et al., 2014. hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell 15, 559–573. Danjo, T., Eiraku, M., Muguruma, K., Watanabe, K., Kawada, M., Yanagawa, Y., Rubenstein, J.L., Sasai, Y., 2011. Subregional specification of embryonic stem cellderived ventral telencephalic tissues by timed and combinatory treatment with extrinsic signals. J. Neurosci.: Off. J. Soc. Neurosci. 31, 1919–1933. de Carlos, J.A., López-Mascaraque, L., Valverde, F., 1996. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J. Neurosci. 16, 6146–6156. DeDiego, I., Smith-Fernandez, A., Fairen, A., 1994. Cortical cells that migrate beyond area boundaries: characterization of an early neuronal population in the lower intermediate zone of prenatal rats. Eur. J. Neurosci. 6, 983–997. DeFelipe, J., Lopez-Cruz, P.L., Benavides-Piccione, R., Bielza, C., Larranaga, P., Anderson, S., Burkhalter, A., Cauli, B., Fairen, A., Feldmeyer, D., et al., 2013. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 14, 202–216. Ding, S., Schultz, P.G., 2004. A role for chemistry in stem cell biology. Nat. Biotechnol. 22, 833–840. Ding, S., Wu, T.Y., Brinker, A., Peters, E.C., Hur, W., Gray, N.S., Schultz, P.G., 2003. Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. USA 100, 7632–7637. Du, T., Xu, Q., Ocbina, P.J., Anderson, S.A., 2008. NKX2.1 specifies cortical
281
interneuron fate by activating Lhx6. Development 135, 1559–1567. Flames, N., Pla, R., Gelman, D.M., Rubenstein, J.L., Puelles, L., Marin, O., 2007. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci.: Off. J. Soc. Neurosci. 27, 9682–9695. Flandin, P., Zhao, Y., Vogt, D., Jeong, J., Long, J., Potter, G., Westphal, H., Rubenstein, J. L., 2011. Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron 70, 939–950. Fragkouli, A., van Wijk, N.V., Lopes, R., Kessaris, N., Pachnis, V., 2009. LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons. Development 136, 3841–3851. Gelman, D.M., Martini, F.J., Nobrega-Pereira, S., Pierani, A., Kessaris, N., Marin, O., 2009. The embryonic preoptic area is a novel source of cortical GABAergic interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 29, 9380–9389. Glickstein, S.B., Alexander, S., Ross, M.E., 2007a. Differences in cyclin D2 and D1 protein expression distinguish forebrain progenitor subsets. Cereb. Cortex 17, 632–642. Glickstein, S.B., Monaghan, J.A., Koeller, H.B., Jones, T.K., Ross, M.E., 2009. Cyclin D2 is critical for intermediate progenitor cell proliferation in the embryonic cortex. J. Neurosci.: Off. J. Soc. Neurosci. 29, 9614–9624. Glickstein, S.B., Moore, H., Slowinska, B., Racchumi, J., Suh, M., Chuhma, N., Ross, M. E., 2007b. Selective cortical interneuron and GABA deficits in cyclin D2-null mice. Development 134, 4083–4093. Gonchar, Y., Wang, Q., Burkhalter, A., 2007. Multiple distinct subtypes of GABAergic neurons in mouse visual cortex identified by triple immunostaining. Front. Neuroanat. 1, 3. Goulburn, A.L., Alden, D., Davis, R.P., Micallef, S.J., Ng, E.S., Yu, Q.C., Lim, S.M., Soh, C. L., Elliott, D.A., Hatzistavrou, T., et al., 2011. A targeted NKX2.1 human embryonic stem cell reporter line enables identification of human basal forebrain derivatives. Stem Cells 29, 462–473. Goulburn, A.L., Stanley, E.G., Elefanty, A.G., Anderson, S.A., 2012. Generating GABAergic cerebral cortical interneurons from mouse and human embryonic stem cells. Stem Cell Res. 8, 416–426. Gulacsi, A., Anderson, S.A., 2006. Shh maintains Nkx2.1 in the MGE by a Gli3-independent mechanism. Cereb. Cortex 16 (Suppl 1), i89–i95. Hansen, D.V., Lui, J.H., Flandin, P., Yoshikawa, K., Rubenstein, J.L., Alvarez-Buylla, A., Kriegstein, A.R., 2013. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences. Nat. Neurosci 16, 1576–1587. Hebert, J.M., Fishell, G., 2008. The genetics of early telencephalon patterning: some assembly required. Nat. Rev. Neurosci 9, 678–685. Inan, M., Petros, T.J., Anderson, S.A., 2013. Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia. Neurobiol. Dis. 53, 36–48. Kanatani, S., Yozu, M., Tabata, H., Nakajima, K., 2008. COUP-TFII is preferentially expressed in the caudal ganglionic eminence and is involved in the caudal migratory stream. J. Neurosci.: Off. J. Soc. Neurosci. 28, 13582–13591. Kawaguchi, Y., Kubota, Y., 1997. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486. Kepecs, A., Fishell, G., 2014. Interneuron cell types are fit to function. Nature 505, 318–326. Kessaris, N., Magno, L., Rubin, A.N., Oliveira, M.G., 2014. Genetic programs controlling cortical interneuron fate. Curr. Opin. Neurobiol. 26, 79–87. Kim, T.G., Yao, R., Monnell, T., Cho, J.H., Vasudevan, A., Koh, A., Peeyush, K.T., Moon, M., Datta, D., Bolshakov, V.Y., et al., 2014. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cells 32, 1789–1804. Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., et al., 2002. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J. Clin. Investig. 109, 475–480. Lavdas, A.A., Grigoriou, M., Pachnis, V., Parnavelas, J.G., 1999. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J. Neurosci. 19, 7881–7888. Letinic, K., Kostovic, I., 1998. Postnatal development of calcium-binding proteins calbindin and parvalbumin in human visual cortex. Cereb. Cortex 8, 660–669. Lewis, D.A., Curley, A.A., Glausier, J.R., Volk, D.W., 2012. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35, 57–67. Li, X.J., Zhang, X., Johnson, M.A., Wang, Z.B., Lavaute, T., Zhang, S.C., 2009. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development 136, 4055–4063. Liodis, P., Denaxa, M., Grigoriou, M., Akufo-Addo, C., Yanagawa, Y., Pachnis, V., 2007. Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J. Neurosci.: Off. J. Soc. Neurosci. 27, 3078–3089. Liu, Y., Weick, J.P., Liu, H., Krencik, R., Zhang, X., Ma, L., Zhou, G.M., Ayala, M., Zhang, S.C., 2013. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat. Biotechnol. 31, 440–447. Lodato, S., Tomassy, G.S., De Leonibus, E., Uzcategui, Y.G., Andolfi, G., Armentano, M., Touzot, A., Gaztelu, J.M., Arlotta, P., Menendez de la Prida, L., et al., 2011. Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy. J. Neurosci.: Off. J. Soc. Neurosci. 31, 4650–4662. Ma, T., Wang, C., Wang, L., Zhou, X., Tian, M., Zhang, Q., Zhang, Y., Li, J., Liu, Z., Cai, Y., et al., 2013. Subcortical origins of human and monkey neocortical interneurons.
282
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
Nat. Neurosci. 16, 1588–1597. Maisano, X., Litvina, E., Tagliatela, S., Aaron, G.B., Grabel, L.B., Naegele, J.R., 2012. Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy. J. Neurosci.: Off. J. Soc. Neurosci. 32, 46–61. Marin, O., 2012. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120. Marin, O., Anderson, S.A., Rubenstein, J.L., 2000. Origin and molecular specification of striatal interneurons. J. Neurosci. 20, 6063–6076. Marin, O., Rubenstein, J.L., 2001. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2, 780–790. Maroof, A.M., Brown, K., Shi, S.H., Studer, L., Anderson, S.A., 2010. Prospective isolation of cortical interneuron precursors from mouse embryonic stem cells. J. Neurosci.: Off. J. Soc. Neurosci. 30, 4667–4675. Maroof, A.M., Keros, S., Tyson, J.A., Ying, S.W., Ganat, Y.M., Merkle, F.T., Liu, B., Goulburn, A., Stanley, E.G., Elefanty, A.G., et al., 2013. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559–572. McKinsey, G.L., Lindtner, S., Trzcinski, B., Visel, A., Pennacchio, L.A., Huylebroeck, D., Higashi, Y., Rubenstein, J.L., 2013. Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons. Neuron 77, 83–98. Miyoshi, G., Hjerling-Leffler, J., Karayannis, T., Sousa, V.H., Butt, S.J., Battiste, J., Johnson, J.E., Machold, R.P., Fishell, G., 2010. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 30, 1582–1594. Miyoshi, G., Young, A., Petros, T., Karayannis, T., McKenzie Chang, M., Lavado, A., Iwano, T., Nakajima, M., Taniguchi, H., Huang, Z.J., et al., 2015. Prox1 regulates the subtype-specific development of caudal ganglionic eminence-derived GABAergic cortical interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 35, 12869–12889. Nicholas, C.R., Chen, J., Tang, Y., Southwell, D.G., Chalmers, N., Vogt, D., Arnold, C.M., Chen, Y.J., Stanley, E.G., Elefanty, A.G., et al., 2013. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573–586. Nobrega-Pereira, S., Kessaris, N., Du, T., Kimura, S., Anderson, S.A., Marin, O., 2008. Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron 59, 733–745. Petros, T.J., Bultje, R.S., Ross, M.E., Fishell, G., Anderson, S.A., 2015. Apical vs. basal neurogenesis directs cortical interneuron subclass fate. Cell. Rep. 13, 1090–1095, in press. Petros, T.J., Maurer, C.W., Anderson, S.A., 2013. Enhanced derivation of mouse ESCderived cortical interneurons by expression of Nkx2.1. Stem Cell Res. 11, 647–656. Rubin, A.N., Kessaris, N., 2013. PROX1: a lineage tracer for cortical interneurons originating in the lateral/caudal ganglionic eminence and preoptic area. PLoS One 8, e77339. Rudy, B., Fishell, G., Lee, S., Hjerling-Leffler, J., 2011. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61. Sheth, A.N., Bhide, P., 1997. Concurrent cellular output from two proliferative populations in the early embryonic mouse corpus striatum. J. Comp. Neurol. 383, 220–230. Somogyi, P., 1977. A specific'axo-axonal' interneuron in the visual cortex of the rat.
Brain Res. 136, 345–350. Sousa, V.H., Miyoshi, G., Hjerling-Leffler, J., Karayannis, T., Fishell, G., 2009. Characterization of Nkx6-2-derived neocortical interneuron lineages. Cereb. Cortex 19 (Suppl 1), i1–10. Southwell, D.G., Nicholas, C.R., Basbaum, A.I., Stryker, M.P., Kriegstein, A.R., Rubenstein, J.L., Alvarez-Buylla, A., 2014. Interneurons from embryonic development to cell-based therapy. Science 344. Tamamaki, N., Fujimori, K.E., Takauji, R., 1997. Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J. Neurosci. 17, 8313–8323. Tamamaki, N., Yanagawa, Y., Tomioka, R., Miyazaki, J., Obata, K., Kaneko, T., 2003. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J. Comp. Neurol. 467, 60–79. Tomishima, M.J., Hadjantonakis, A.K., Gong, S., Studer, L., 2007. Production of green fluorescent protein transgenic embryonic stem cells using the GENSAT bacterial artificial chromosome library. Stem Cells 25, 39–45. Tricoire, L., Pelkey, K.A., Daw, M.I., Sousa, V.H., Miyoshi, G., Jeffries, B., Cauli, B., Fishell, G., McBain, C.J., 2010. Common origins of hippocampal Ivy and nitric oxide synthase expressing neurogliaform cells. J. Neurosci.: Off. J. Soc. Neurosci. 30, 2165–2176. Tyson, J.A., Anderson, S.A., 2014. GABAergic interneuron transplants to study development and treat disease. Trends Neurosci. 37, 169–177. Tyson, J.A., Goldberg, E.M., Maroof, A.M., Petros, T.P., Anderson, S.A., 2015. Duration of culture and Sonic Hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells. Development 142, 1267–1278. Watanabe, K., Kamiya, D., Nishiyama, A., Katayama, T., Nozaki, S., Kawasaki, H., Watanabe, Y., Mizuseki, K., Sasai, Y., 2005. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci. 8, 288–296. Watanabe, K., Ueno, M., Kamiya, D., Nishiyama, A., Matsumura, M., Wataya, T., Takahashi, J.B., Nishikawa, S., Muguruma, K., Sasai, Y., 2007. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol. 25, 681–686. Wonders, C.P., Taylor, L., Welagen, J., Mbata, I.C., Xiang, J.Z., Anderson, S.A., 2008. A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. Dev. Biol. 314, 127–136. Xu, Q., Cobos, I., De La Cruz, E., Rubenstein, J.L., Anderson, S.A., 2004. Origins of cortical interneuron subtypes. J. Neurosci.: Off. J. Soc. Neurosci. 24, 2612–2622. Xu, Q., Guo, L., Moore, H., Waclaw, R.R., Campbell, K., Anderson, S.A., 2010a. Sonic hedgehog signaling confers ventral telencephalic progenitors with distinct cortical interneuron fates. Neuron 65, 328–340. Xu, Q., Tam, M., Anderson, S.A., 2008. Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J. Comp. Neurol. 506, 16–29. Xu, Q., Wonders, C.P., Anderson, S.A., 2005. Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon. Development 132, 4987–4998. Xu, X., Roby, K.D., Callaway, E.M., 2010b. Immunochemical characterization of inhibitory mouse cortical neurons: three chemically distinct classes of inhibitory cells. J. Comp. Neurol. 518, 389–404. Zhao, Y., Flandin, P., Long, J.E., Cuesta, M.D., Westphal, H., Rubenstein, J.L., 2008. Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants. J. Comp. Neurol. 510, 79–99.
Contents lists available at ScienceDirect
Brain Research journal homepage: www.elsevier.com/locate/brainres
Review
Fate determination of cerebral cortical GABAergic interneurons and their derivation from stem cells Erik M. DeBoer, Stewart A. Anderson n Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania, School of Medicine, 3615 Civic Center Blvd, ARC 517, Philadelphia, PA 19104-5127, USA
art ic l e i nf o
a b s t r a c t
Article history: Accepted 15 December 2015 Available online 23 December 2015
Cortical GABAergic interneurons modulate cortical excitation, and their dysfunction is implicated in a multitude of neuropsychiatric disorders including autism, schizophrenia and epilepsy. Consequently, the study of cortical interneuron development, and their derivation from stem cells for transplantation therapy, has garnered intense scientific interest. In this review, we discuss some of the molecular signals involved in cortical interneuron fate determination, and describe how this has informed the use of mouse and human embryonic stem cell biology in generating cortical interneurons in vitro. We highlight the tremendous progress that has been made recently using stem cells to derive cortical interneurons, as well as challenges that have arisen. This article is part of a Special Issue entitled SI:StemsCellsinPsychiatry. & 2016 Published by Elsevier B.V.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origins of cortical interneurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cortical interneuron fate determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. MGE derived interneurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Interneuron generation outside the MGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Generation of interneurons from pluripotent stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mouse embryonic stem cells (mESCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Human stem cells (hESCs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction GABAergic cortical interneurons, also called local circuit neurons (LCNs) can be segregated into at least three categories based on protein marker expression, morphology and electrophysiological characteristics (Ascoli et al., 2008; DeFelipe et al., 2013; Kawaguchi and Kubota, 1997; Rudy et al., 2011). The first group, parvalbuminpositive (PV) interneurons, are fast spiking, minimally accommodating, and can be subdivided morphologically into at least two n
Corresponding author. E-mail addresses: [email protected] (E.M. DeBoer), [email protected] (S.A. Anderson). http://dx.doi.org/10.1016/j.brainres.2015.12.031 0006-8993/& 2016 Published by Elsevier B.V.
277 278 278 278 278 279 279 279 281
groups: chandelier and basket cells. Basket cells innervate pyramidal neurons as well as other interneurons at the proximal dendritic segments and cell body (Kepecs and Fishell, 2014). PVpositive chandelier cells preferentially innervate the axon initial segment of pyramidal neurons (Somogyi, 1977). The second group of interneurons express the neuropeptide somatostatin (SST), tend to innervate the distal dendrite of pyramidal neurons and some interneurons, and fire action potentials in bursting or in accommodating patterns. The final, 5HT3aR-expressing interneuron subgroup is highly diverse in morphology, axon targeting and physiological characteristics (Miyoshi et al., 2010). Cortical interneurons serve to modulate the firing of glutamatergic projection neurons as well as other interneurons, such that disruption of interneuron
278
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
distribution and wiring is associated with neuropsychiatric disorders, including autism, schizophrenia and epilepsy (Marin, 2012).
2. Origins of cortical interneurons Cortical GABAergic interneurons are born in the subpallial (ventral) forebrain, in the ganglionic eminences (MGE; LGE and CGE) (Anderson et al., 1997b; Brunstrom et al., 1997; de Carlos et al., 1996; DeDiego et al., 1994; Hansen et al., 2013; Ma et al., 2013; Tamamaki et al., 1997). After cell cycle exit, they undergo a longer, non-radial migration into the developing cortical plate than excitatory cortical projection neurons, which originate in the dorsal telencephalon and migrate along radial glial fibers. It is unclear why cortical pyramidal neurons and interneurons have distinct origins; although cortical evolution may have followed a path of importation of GABAergic cells from the predominantly GABA-producing subpallium rather than evolving the capacity for pallial neuroepithelium to produce GABAergic in addition to glutamatergic neurons (Marin and Rubenstein, 2001).
3. Cortical interneuron fate determination 3.1. MGE derived interneurons The majority of cortical interneurons are SST or PV expressing (Gonchar et al., 2007; Tamamaki et al., 2003; Xu et al., 2010b), and originate from Nkx2.1-expressing progenitors in the MGE and in the preoptic region (Butt et al., 2005; Gelman et al., 2009; Xu et al., 2004, 2008). In the ventral forebrain, sonic Hedgehog (Shh) is required for development, including the induction of Nkx2.1. (Hebert and Fishell, 2008). Interestingly, after initial patterning is established, Shh remains necessary for the maintenance of Nkx2.1 expression in mitotic progenitors of the MGE but not in their post-mitotic progeny (Gulacsi and Anderson, 2006; Xu et al., 2010a, 2005). This Nkx2.1 maintenance role underlies a remarkable plasticity of MGE progenitors to generate different interneuron subgroups depending on conditions. For example, MGE progenitors in which Shh signaling is eliminated in vivo can switch fates from that of MGE-derived PV or SST expressing interneurons, to typically CGE-derived bipolar, calretinin-expressing interneurons (Xu et al., 2010a). Such plasticity has important implications for the derivation of cortical interneurons from pluripotent stem cells, as discussed below. Although in most of the developing neuraxis, Shh signaling occurs in a gradient of ventral-high, dorsal-low, in the MGE this signaling is more complex. The dorsal region of the MGE expresses multiple markers indicative of high levels of Shh signaling, including Patched-1 and Gli1, relative to more ventral MGE regions (Wonders et al., 2008). Cortical transplantations of progenitors from this dorsal region, particularly earlier in neurogenesis (i.e. before E14.5), are enriched for SST interneurons relative to those expressing PV (Flames et al., 2007; Wonders et al., 2008; Xu et al., 2010a). Correspondingly, experiments in both transgenic mice and in mouse stem cells indicate that while some Shh signaling is required to maintain Nkx2.1 expression and thus MGE interneuron fate, higher levels favor the generation of SST interneurons over those expressing PV (Tyson et al., 2015; Xu et al., 2010a). How this effect is mediated remains unclear, although the Shh signaling target gene Nkx6.2 is selectively expressed in the dorsal-most MGE, and its loss results in a modest reduction of SST-expressing interneurons (Sousa et al., 2009). In addition to Shh signaling (SST-specified at higher levels, PV specified at lower levels), location within the MGE (SST biased to originate from the dorsal MGE, PV biased to originate from more ventral MGE), and time (SST biased to originate earlier in neurogenesis
and to occupy deeper cortical layers, PV biased to originate later in neurogenesis and to occupy more superficial cortical layers), another factor has been shown to critically influence MGE-derived interneuron fate determination. The periventricular proliferative zone of the developing telencephalon contains two domains, defined histologically as the ventricular zone and subventricular zone (Committee, 1970), or defined in terms of proliferative populations in a variety of ways, including apical (i.e. along the ventricular surface) or basal (i.e. abventricular) (Caviness et al., 2009). In the developing striatum, neurogenesis from abventricular mitoses is extensive remarkably early, (Sheth and Bhide, 1997), and neurogenesis in the VZ versus SVZ appears to result in the generation of distinct compartments of striatal projection neurons (Anderson et al., 1997a). Loss of cyclin D2, which is expressed by abventricular progenitors in the MGE and throughout the telencephalon, results in a relatively selective reduction of cortical PV interneurons compared to the SST subgroup (Glickstein et al., 2007a; Glickstein et al., 2007b). In contrast, loss of CoupTf2 increases cyclin D2 in the dorsal MGE and results in excess production of PV interneurons (Lodato et al., 2011). Finally, a recent study using in vivo fate mapping and fate manipulation of MGE progenitors demonstrated that apical neurogenesis in the MGE is strongly biased to produce SST interneurons, whereas basal neurogenesis generates mainly PV interneurons (Petros et al., 2015). Since ventricular zone neurogenic divisions tend to be asymmetric (generating one neuron and one progenitor), and SVZ divisions tend to be symmetric (generating either two progenitors or two neurons)(Glickstein et al., 2009), these results suggest that the mode of division also has a critical influence on interneuron fate determination (Petros et al., 2015). Downstream of Nkx2.1 in the MGE, several factors have been identified that influence cortical interneuron fate determination. Nkx2.1 itself is maintained in GABAergic interneurons fated for the striatum, and is downregulated in those fated for the cerebral cortex (Nobrega-Pereira et al., 2008). This striatal-cortical interneuron fate decision is also critically influenced by the transcription factors Dlx1 and Dlx2, and their regulation of Zfhx1b (McKinsey et al., 2013). Around the time of cell cycle exit, Nkx2.1 directly activates Lhx6 (Du et al., 2008), which is maintained in most MGE-derived interneurons throughout their post-mitotic lives and is required for their normal migration and post-migratory maturation (Flandin et al., 2011; Fragkouli et al., 2009; Lavdas et al., 1999; Liodis et al., 2007; Zhao et al., 2008). Downstream of Lhx6, the transcription factor Sox6 is also required for normal PV and SST interneuron development (Azim et al., 2009; Batista-Brito et al., 2009), as is Satb1. (Close et al., 2012). While a large number of additional intrinsic and extrinsic factors have been identified that influence interneuron migration, maturation, and integration into cortical circuitry, this process has been reviewed recently and is outside the scope of this review (Kepecs and Fishell, 2014; Kessaris et al., 2014). 3.2. Interneuron generation outside the MGE Outside of the Nkx2.1-expressing proliferative domains of the MGE and preoptic area, other subcortical regions of the telencephalon produce the remaining portion of cortical LCNs, and recent findings demonstrate that most of these lineages can be traced through their expression of Prox1 (Rubin and Kessaris, 2013). Several subtypes of LCNs are generated from CGE progenitors, including subsets of those expressing neuropeptide Y (NPY), Reelin, and calretinin (Butt et al., 2005; Miyoshi et al., 2010). In addition, CGEgenerated LCN subgroups all express the serotonin receptor 5HT3aR (Tricoire et al., 2010), and VIP is a fairly selective marker for a subset of CGE derived, vertically oriented, bipolar interneurons (Miyoshi et al., 2010). A small proportion of cortical interneurons also appear to have their mitotic origin in the LGE (Anderson et al., 2001; Cai et al., 2013). Regarding fate determination of CGE-derived
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
interneurons, this diverse group has been studied less thoroughly than those from the MGE, but Gsx2, CoupTF2, and Prox1 all have been implicated in CGE interneuron fate determination (Kanatani et al., 2008; Lodato et al., 2011; Miyoshi et al., 2015; Xu et al., 2010a). In addition, Fgf15/19 signaling enhanced the generation of CGE-like over MGE-like cortical interneurons from mouse embryonic stem cells (Danjo et al., 2011).
4. Generation of interneurons from pluripotent stem cells 4.1. Mouse embryonic stem cells (mESCs) Aberrations in GABA signaling and interneuron function have been implicated in the etiology of a variety of neuropsychiatric illnesses, prompting efforts to treat such conditions using interneuronbased transplantation therapies, reviewed in (Southwell et al., 2014; Tyson and Anderson, 2014). Promising preclinical results using interneuron transplantation therapy for “interneuronopathies” have stimulated keen interest in generating cortical interneurons from a theoretically unlimited and potentially patient-derived source: stem cells. Early attempts to generate interneurons began using mouse embryonic stem cells (mESCs) over 10 years ago. These investigations sought to mimic the developmental environment of stem cells in order to influence mESC differentiation into neuronal subtypes (Ding and Schultz, 2004; Ding et al., 2003). A subsequent study made a major breakthrough in demonstrating that WNT inhibition enhanced the generation of Foxg1expressing telencephalic progenitors, with the later addition of Shh producing some Nkx2.1-expressing progenitors (Watanabe et al., 2005). Here, stem cells were initially differentiated as floating embryoid bodies, then landed to generate an adherent culture. However, this protocol was more efficient at generating Pax6þ (cortex-like) progenitors than it was at producing Nkx2.1positive (MGE-like) progenitors (roughly 75% vs 40% respectively), and although some cells maintained in culture eventually expressed GABA, it was not clear whether these were cortical interneurons versus other GABAergic populations. Building on this work, and benefiting from an approach to modify embryonic stem cells with modified bacterial artificial chromosomes that allow better tissue-selective expression of fluorescent reporter constructs (Tomishima et al., 2007), investigators generated Lhx6-GFP mESC line (Maroof et al., 2010). Although induction of Foxg1 (telencephalic), Nkx2.1 (MGE-like, as Nkx2.1 but not Foxg1 is also expressed in hypothalamus), and Lhx6 remained at less than 5%, the ability to isolate newly postmitotic, putatively GABAergic interneuron-fated cells by FACS allowed for definitive demonstration of their MGE-interneuron like fates after transplantation into neonatal mouse neocortex. Both PV and SSTexpressing cells with interneuron-like morphologies and the appropriate subgroup selective electrophysiologies were identified in cortical slices 30 days after transplantation. Danjo et al., using a Foxg1-reporter line to optimize the generation of telencephaliclike progenitors, also extended the basic approach in Watanabe (2005) to find that the signaling molecule Fgf8 enhanced the generation of MGE-like interneurons, whereas Fgf15/19 enhanced the generation of CGE-like interneurons (Danjo et al., 2011). Of note, Shh signaling inhibition by the Tgf-β agonist activin can also direct ventralized mESC differentiations to bipolar calretinin expressing, CGE-like interneurons (Cambray et al., 2012), a result remarkably consistent with the fate-switching effects of Shh inhibition in the MGE in vivo (Xu et al., 2010a). Subsequent studies used reporter-expressing mouse ESCs to study the regulation of interneuron fate. Viral infection of the Lhx6-GFP line with mCherry-tagged Dlx1/2 enhancer elements allowed for the identification of shifting enhancer activation
279
during the transition from Olig2 þ interneuron progenitor to Lhx6þ postmitotic interneuron (Chen et al., 2013). Another group used the Lhx6-GFP BAC and modification of a bicistronic tet-inducible element to demonstrate that forced induction of Nkx2.1 can enhance the generation of Lhx6þ interneurons in the absence of Shh signaling (Petros et al., 2013). A similar but more elegant approach to using mESCs in the study of the transcriptional regulation of interneuron fate involved forced expression of Nkx2.1 by the nestin promoter (expressed in neural progenitors), together with a bicistronic tet-inducible construct to drive two genes of interest and a Dlx5/6-GFP reporter of GABAergic fate (Au et al., 2013). This study was the first to enhance the derivation of MGEderived interneuron subgroups, increasing the generation of PVþ interneurons relative to those expressing SST by the induced expression of Nkx2.1, Dlx2, and Lmo3. A subsequent study that remodified the Lhx6-GFP mESC line with an Nkx2.1-mCherry reporter, also described significant enrichments of either SST or PVexpressing interneurons by modifications of Shh exposure, time in culture, and sorting for Nkx2.1-mCherry (in which case the cells are identified after transplantation by their subsequent expression of Lhx6-GFP) versus Lhx6-GFP (Tyson and Anderson 2014). In sum, studies of directed differentiation of mESCs to cortical interneuron-like cells are finding that recapitulation of normal development in vitro can result in the generation of apparently “real” interneurons. An important caveat to this statement is that characterization of mESC-derived interneurons to date has at best been at the levels of neurochemical expression and action potential discharge pattern following current injection, and not at the level of specificity of axonal or dendritic connectivity. It should also be noted that transplantation itself, rather than an intrinsic failing of the mESC-derived interneurons to accurately differentiate, could result in differences between in vivo and in vitroderived interneurons. Be that as it may, this system is now being used by multiple groups to study the regulation of interneuron fate determination. Although at the time of writing this review the authors are not aware of publications using mESC-derived interneurons in transplantation studies to treat disease models, at least one paper has demonstrated the feasibility of such a study (Maisano et al., 2012). Importantly, and bolstered by advances in generating cortical interneuron-like cells from mESCs, the generation of these cells from human stem cells is yielding promising results in the development of cell based therapies. 4.2. Human stem cells (hESCs) The generation of cortical interneuron-like cells from human pluripotent stem cells originally lagged behind that of mouse studies, owing mainly to the far slower pace of differentiation of human stem cells, their tendency to die after replating, and the lack of approaches for purifying interneuron progenitors or post-mitotic precursors from the mixed populations that occur with any protocol. While a group of studies demonstrated the capacity of human stem cells to generate rostral-forebrain (telencephalic-like) progenitors (Goulburn et al., 2012), three studies were particularly critical in moving the field forward. First, the group of Sasai found that addition of the Rho-associated kinase (ROCK) inhibitor, Y-27632, greatly reduces apoptosis at passaging (Watanabe et al., 2007). Second, it was demonstrated that, as occurs in vivo and in mouse ESC protocols, differential Shh and Wnt signaling agonism or antagonism can be used to drive telencephalon-enriched (Foxg1þ) hESC derived cultures into cortical-like (Pax6þ , Emx1þ) or MGElike (Nkx2.1þ) progenitor fields (Li et al., 2009). These cells also showed capacity to differentiate into glutamatergic or GABAergic neurons. Third, it was shown that, by dual inhibition of the TGF-β pathway with the peptide noggin (replaceable by the small molecule LDN) and the small molecule SB431542, during initial phase of
280
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
differentiation, it was possible to rapidly obtain neural progenitors (Chambers et al., 2009). Early inhibition of WNT signaling, following the lead initially demonstrated by the group of Sasai on mESCs (Watanabe et al., 2005), to the “dual-smad” approach has led to the relatively rapid, relatively uniform generation of telencephalon-like progenitors. These progenitors can then be dorsalized or ventralized into a variety of telencephalic subfields and differentiated into a variety of neuronal subgroups, including putative cortical interneurons (Kim et al., 2014; Maroof et al., 2013; Nicholas et al., 2013). Progress in optimizing protocols for the generation of cortical interneurons from human stem cells received a significant boost when the Elefanty/Stanley group used homologous recombination to create a hESC line expressing GFP from the NKX2.1 locus (Goulburn et al., 2011). Drawbacks of this line include its heterozygosity for NKX2.1, which is associated with a movement disorder (Breedveld et al., 2002; Krude et al., 2002), and its NIH non-registry background. There was also a tendency for tumor development, although one group cleverly obviated this problem by FACS for both NKX2.1-GFP and PSA-NCAM (Nicholas et al., 2013). In addition, NKX2.1 is downregulated by most cortical interneurons prior to their migration into the neocortex, in both mice and humans (Hansen et al., 2013; Ma et al., 2013; Marin et al., 2000). However, this downregulation occurs over a period of at least 6 months following transplantation of hESC-derived MGE-like cells into the neocortex of immune-suppressed mice, such that the line has been used to generate large numbers of neurons with migratory, morphological, synaptic, electrophysiological, and neurochemical features consistent with an immature interneuron fate (Maroof et al., 2013; Nicholas et al., 2013). While these studies are highly promising, they underscore two major challenges to the generation of cortical interneurons from human stem cells. First is the protracted maturation of the human cells following xenograft. Interestingly, maturation appears to occur more quickly when the
human interneuron precursors are cultured with a mixed layer of rodent cortical neurons and astrocytes (Maroof et al., 2013), than when cultured on astrocytes alone (Nicholas et al., 2013). This mixed co-culture system should be amenable to mechanistic studies of human interneuron synaptogenesis and initial electrophysiological maturation in vitro. Second, both studies found few cells that differentiated into PV-expressing interneurons, which is perhaps the most illness-related subclass (Inan et al., 2013; Lewis et al., 2012; Marin, 2012). This was suggested to be secondary to the delayed maturation of human interneurons, which is a reasonable idea given that PV expression by cortical interneurons in primates is minimal until after birth (Anderson et al., 1995; Letinic and Kostovic, 1998). A recent study, however, demonstrated with mESCs that it is also quite possible that the protocols being used favor SST or PV interneurons due to their relatively high level of Shh (Tyson et al., 2015). Evidence in mouse established PV interneurons are generated primarily from subventricular zone divisions of cyclin D2-expressing progenitors (Petros et al., 2015). This may provide additional insights that could be applied to strategies for enriching generation of PV interneurons from hESCs. Despite the challenges to generating efficient reagents and protocols for making cortical interneurons from hESCs, two recent studies have demonstrated the efficacy of these cells for treating seizures in a rodent model (Cunningham et al., 2014; Liu et al., 2013). As interneuron-based transplantation therapies are covered elsewhere in this issue, these studies will not be elaborated upon here. However, it should be evident that tremendous progress has been made in generating cortical interneuron-like cells from both mouse and human stem cells. We can expect to see a shift from studies that emphasize better ways to make such cells, to studies that use this system for the study of normal and pathological development, and for the treatment interneuron related disease (Fig. 1).
Fig. 1. Above: A table representing the small molecules, recombinant proteins and genetic expression of molecules used in recent literature for (top row) maintaining ESCs (middle row) inducing MGE-like ventral forebrain progenitors and (bottom row) neuronal differentiation. Below: A schematic of interneuron fate determination in vivo. PVpositive interneurons are preferentially born in the dorsal region of the MGE, where SST-positive interneurons are born from the ventral MGE. WNT and BMP signaling is higher in the developing dorsal forebrain, therefore inhibitors of these pathways are often employed in interneuron differentiation protocols to ventralize progenitors. While the SHH gradient is higher ventrally than dorsally in the developing forebrain, evidence suggests that this gradient is reversed within the MGE. The SHH-high, dorsal MGE gives rise to early-born SST-interneurons which migrate more often to deep layers of the developing cortex, whereas the SHH-poor ventral MGE more often produces later born, PV-positive interneurons which are enriched in superficial layers. FGF15/19 appear to inhibit rostral identity and favor CGE lineages by inhibiting FGF8. Reciprocally, FGF8 has been employed to rostralized ventral forebrain progenitors in both hESC and mESC protocols.
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
References Anderson, S.A., Classey, J.D., Conde, F., Lund, J.S., Lewis, D.A., 1995. Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience 67, 7–22. Anderson, S.A., Eisenstat, D.D., Shi, L., Rubenstein, J.L., 1997b. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278, 474–476. Anderson, S.A., Marin, O., Horn, C., Jennings, K., Rubenstein, J.L., 2001. Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128, 353–363. Anderson, S.A., Qiu, M., Bulfone, A., Eisenstat, D.D., Meneses, J., Pedersen, R., Rubenstein, J.L., 1997a. Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. Neuron 19, 27–37. Ascoli, G.A., Alonso-Nanclares, L., Anderson, S.A., Barrionuevo, G., Benavides-Piccione, R., Burkhalter, A., Buzsaki, G., Cauli, B., Defelipe, J., Fairen, A., et al., 2008. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568. Au, E., Ahmed, T., Karayannis, T., Biswas, S., Gan, L., Fishell, G., 2013. A modular gainof-function approach to generate cortical interneuron subtypes from ES cells. Neuron 80, 1145–1158. Azim, E., Jabaudon, D., Fame, R.M., Macklis, J.D., 2009. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nat. Neurosci. 12, 1238–1247. Batista-Brito, R., Rossignol, E., Hjerling-Leffler, J., Denaxa, M., Wegner, M., Lefebvre, V., Pachnis, V., Fishell, G., 2009. The cell-intrinsic requirement of Sox6 for cortical interneuron development. Neuron 63, 466–481. Breedveld, G.J., van Dongen, J.W., Danesino, C., Guala, A., Percy, A.K., Dure, L.S., Harper, P., Lazarou, L.P., van der Linde, H., Joosse, M., et al., 2002. Mutations in TITF-1 are associated with benign hereditary chorea. Hum. Mol. Genet. 11, 971–979. Brunstrom, J.E., Gray-Swain, M.R., Osborne, P.A., Pearlman, A.L., 1997. Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4. Neuron 18, 505–517. Butt, S.J., Fuccillo, M., Nery, S., Noctor, S., Kriegstein, A., Corbin, J.G., Fishell, G., 2005. The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron 48, 591–604. Cai, Y., Zhang, Q., Wang, C., Zhang, Y., Ma, T., Zhou, X., Tian, M., Rubenstein, J.L., Yang, Z., 2013. Nuclear receptor COUP-TFII-expressing neocortical interneurons are derived from the medial and lateral/caudal ganglionic eminence and define specific subsets of mature interneurons. J. Comp. Neurol. 521, 479–497. Cambray, S., Arber, C., Little, G., Dougalis, A.G., de Paola, V., Ungless, M.A., Li, M., Rodriguez, T.A., 2012. Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors. Nat. Commun. 3, 841. Caviness Jr., V.S., Nowakowski, R.S., Bhide, P.G., 2009. Neocortical neurogenesis: morphogenetic gradients and beyond. Trends Neurosci. 32, 443–450. Chambers, S.M., Fasano, C.A., Papapetrou, E.P., Tomishima, M., Sadelain, M., Studer, L., 2009. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280. Chen, Y.J., Vogt, D., Wang, Y., Visel, A., Silberberg, S.N., Nicholas, C.R., Danjo, T., Pollack, J.L., Pennacchio, L.A., Anderson, S., et al., 2013. Use of "MGE Enhancers" for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons. PLoS One 8, e61956. Close, J., Xu, H., Garcia, N.D.M., Batista-Brito, R., Rossignol, E., Rudy, B., Fishell, G., 2012. Satb1 is an activity-modulated transcription factor required for the terminal differentiation and connectivity of MGE-derived cortical interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 32, 17690–17705. Committee, B., 1970. Embryonic vertebrate central nervous system: revised termnology. Anat. Rec. 166, 257–261. Cunningham, M., Cho, J.H., Leung, A., Savvidis, G., Ahn, S., Moon, M., Lee, P.K., Han, J. J., Azimi, N., Kim, K.S., et al., 2014. hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell 15, 559–573. Danjo, T., Eiraku, M., Muguruma, K., Watanabe, K., Kawada, M., Yanagawa, Y., Rubenstein, J.L., Sasai, Y., 2011. Subregional specification of embryonic stem cellderived ventral telencephalic tissues by timed and combinatory treatment with extrinsic signals. J. Neurosci.: Off. J. Soc. Neurosci. 31, 1919–1933. de Carlos, J.A., López-Mascaraque, L., Valverde, F., 1996. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J. Neurosci. 16, 6146–6156. DeDiego, I., Smith-Fernandez, A., Fairen, A., 1994. Cortical cells that migrate beyond area boundaries: characterization of an early neuronal population in the lower intermediate zone of prenatal rats. Eur. J. Neurosci. 6, 983–997. DeFelipe, J., Lopez-Cruz, P.L., Benavides-Piccione, R., Bielza, C., Larranaga, P., Anderson, S., Burkhalter, A., Cauli, B., Fairen, A., Feldmeyer, D., et al., 2013. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 14, 202–216. Ding, S., Schultz, P.G., 2004. A role for chemistry in stem cell biology. Nat. Biotechnol. 22, 833–840. Ding, S., Wu, T.Y., Brinker, A., Peters, E.C., Hur, W., Gray, N.S., Schultz, P.G., 2003. Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. USA 100, 7632–7637. Du, T., Xu, Q., Ocbina, P.J., Anderson, S.A., 2008. NKX2.1 specifies cortical
281
interneuron fate by activating Lhx6. Development 135, 1559–1567. Flames, N., Pla, R., Gelman, D.M., Rubenstein, J.L., Puelles, L., Marin, O., 2007. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci.: Off. J. Soc. Neurosci. 27, 9682–9695. Flandin, P., Zhao, Y., Vogt, D., Jeong, J., Long, J., Potter, G., Westphal, H., Rubenstein, J. L., 2011. Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron 70, 939–950. Fragkouli, A., van Wijk, N.V., Lopes, R., Kessaris, N., Pachnis, V., 2009. LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons. Development 136, 3841–3851. Gelman, D.M., Martini, F.J., Nobrega-Pereira, S., Pierani, A., Kessaris, N., Marin, O., 2009. The embryonic preoptic area is a novel source of cortical GABAergic interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 29, 9380–9389. Glickstein, S.B., Alexander, S., Ross, M.E., 2007a. Differences in cyclin D2 and D1 protein expression distinguish forebrain progenitor subsets. Cereb. Cortex 17, 632–642. Glickstein, S.B., Monaghan, J.A., Koeller, H.B., Jones, T.K., Ross, M.E., 2009. Cyclin D2 is critical for intermediate progenitor cell proliferation in the embryonic cortex. J. Neurosci.: Off. J. Soc. Neurosci. 29, 9614–9624. Glickstein, S.B., Moore, H., Slowinska, B., Racchumi, J., Suh, M., Chuhma, N., Ross, M. E., 2007b. Selective cortical interneuron and GABA deficits in cyclin D2-null mice. Development 134, 4083–4093. Gonchar, Y., Wang, Q., Burkhalter, A., 2007. Multiple distinct subtypes of GABAergic neurons in mouse visual cortex identified by triple immunostaining. Front. Neuroanat. 1, 3. Goulburn, A.L., Alden, D., Davis, R.P., Micallef, S.J., Ng, E.S., Yu, Q.C., Lim, S.M., Soh, C. L., Elliott, D.A., Hatzistavrou, T., et al., 2011. A targeted NKX2.1 human embryonic stem cell reporter line enables identification of human basal forebrain derivatives. Stem Cells 29, 462–473. Goulburn, A.L., Stanley, E.G., Elefanty, A.G., Anderson, S.A., 2012. Generating GABAergic cerebral cortical interneurons from mouse and human embryonic stem cells. Stem Cell Res. 8, 416–426. Gulacsi, A., Anderson, S.A., 2006. Shh maintains Nkx2.1 in the MGE by a Gli3-independent mechanism. Cereb. Cortex 16 (Suppl 1), i89–i95. Hansen, D.V., Lui, J.H., Flandin, P., Yoshikawa, K., Rubenstein, J.L., Alvarez-Buylla, A., Kriegstein, A.R., 2013. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences. Nat. Neurosci 16, 1576–1587. Hebert, J.M., Fishell, G., 2008. The genetics of early telencephalon patterning: some assembly required. Nat. Rev. Neurosci 9, 678–685. Inan, M., Petros, T.J., Anderson, S.A., 2013. Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia. Neurobiol. Dis. 53, 36–48. Kanatani, S., Yozu, M., Tabata, H., Nakajima, K., 2008. COUP-TFII is preferentially expressed in the caudal ganglionic eminence and is involved in the caudal migratory stream. J. Neurosci.: Off. J. Soc. Neurosci. 28, 13582–13591. Kawaguchi, Y., Kubota, Y., 1997. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486. Kepecs, A., Fishell, G., 2014. Interneuron cell types are fit to function. Nature 505, 318–326. Kessaris, N., Magno, L., Rubin, A.N., Oliveira, M.G., 2014. Genetic programs controlling cortical interneuron fate. Curr. Opin. Neurobiol. 26, 79–87. Kim, T.G., Yao, R., Monnell, T., Cho, J.H., Vasudevan, A., Koh, A., Peeyush, K.T., Moon, M., Datta, D., Bolshakov, V.Y., et al., 2014. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cells 32, 1789–1804. Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., et al., 2002. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J. Clin. Investig. 109, 475–480. Lavdas, A.A., Grigoriou, M., Pachnis, V., Parnavelas, J.G., 1999. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J. Neurosci. 19, 7881–7888. Letinic, K., Kostovic, I., 1998. Postnatal development of calcium-binding proteins calbindin and parvalbumin in human visual cortex. Cereb. Cortex 8, 660–669. Lewis, D.A., Curley, A.A., Glausier, J.R., Volk, D.W., 2012. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35, 57–67. Li, X.J., Zhang, X., Johnson, M.A., Wang, Z.B., Lavaute, T., Zhang, S.C., 2009. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development 136, 4055–4063. Liodis, P., Denaxa, M., Grigoriou, M., Akufo-Addo, C., Yanagawa, Y., Pachnis, V., 2007. Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J. Neurosci.: Off. J. Soc. Neurosci. 27, 3078–3089. Liu, Y., Weick, J.P., Liu, H., Krencik, R., Zhang, X., Ma, L., Zhou, G.M., Ayala, M., Zhang, S.C., 2013. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat. Biotechnol. 31, 440–447. Lodato, S., Tomassy, G.S., De Leonibus, E., Uzcategui, Y.G., Andolfi, G., Armentano, M., Touzot, A., Gaztelu, J.M., Arlotta, P., Menendez de la Prida, L., et al., 2011. Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy. J. Neurosci.: Off. J. Soc. Neurosci. 31, 4650–4662. Ma, T., Wang, C., Wang, L., Zhou, X., Tian, M., Zhang, Q., Zhang, Y., Li, J., Liu, Z., Cai, Y., et al., 2013. Subcortical origins of human and monkey neocortical interneurons.
282
E.M. DeBoer, S.A. Anderson / Brain Research 1655 (2017) 277–282
Nat. Neurosci. 16, 1588–1597. Maisano, X., Litvina, E., Tagliatela, S., Aaron, G.B., Grabel, L.B., Naegele, J.R., 2012. Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy. J. Neurosci.: Off. J. Soc. Neurosci. 32, 46–61. Marin, O., 2012. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120. Marin, O., Anderson, S.A., Rubenstein, J.L., 2000. Origin and molecular specification of striatal interneurons. J. Neurosci. 20, 6063–6076. Marin, O., Rubenstein, J.L., 2001. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2, 780–790. Maroof, A.M., Brown, K., Shi, S.H., Studer, L., Anderson, S.A., 2010. Prospective isolation of cortical interneuron precursors from mouse embryonic stem cells. J. Neurosci.: Off. J. Soc. Neurosci. 30, 4667–4675. Maroof, A.M., Keros, S., Tyson, J.A., Ying, S.W., Ganat, Y.M., Merkle, F.T., Liu, B., Goulburn, A., Stanley, E.G., Elefanty, A.G., et al., 2013. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559–572. McKinsey, G.L., Lindtner, S., Trzcinski, B., Visel, A., Pennacchio, L.A., Huylebroeck, D., Higashi, Y., Rubenstein, J.L., 2013. Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons. Neuron 77, 83–98. Miyoshi, G., Hjerling-Leffler, J., Karayannis, T., Sousa, V.H., Butt, S.J., Battiste, J., Johnson, J.E., Machold, R.P., Fishell, G., 2010. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 30, 1582–1594. Miyoshi, G., Young, A., Petros, T., Karayannis, T., McKenzie Chang, M., Lavado, A., Iwano, T., Nakajima, M., Taniguchi, H., Huang, Z.J., et al., 2015. Prox1 regulates the subtype-specific development of caudal ganglionic eminence-derived GABAergic cortical interneurons. J. Neurosci.: Off. J. Soc. Neurosci. 35, 12869–12889. Nicholas, C.R., Chen, J., Tang, Y., Southwell, D.G., Chalmers, N., Vogt, D., Arnold, C.M., Chen, Y.J., Stanley, E.G., Elefanty, A.G., et al., 2013. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573–586. Nobrega-Pereira, S., Kessaris, N., Du, T., Kimura, S., Anderson, S.A., Marin, O., 2008. Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron 59, 733–745. Petros, T.J., Bultje, R.S., Ross, M.E., Fishell, G., Anderson, S.A., 2015. Apical vs. basal neurogenesis directs cortical interneuron subclass fate. Cell. Rep. 13, 1090–1095, in press. Petros, T.J., Maurer, C.W., Anderson, S.A., 2013. Enhanced derivation of mouse ESCderived cortical interneurons by expression of Nkx2.1. Stem Cell Res. 11, 647–656. Rubin, A.N., Kessaris, N., 2013. PROX1: a lineage tracer for cortical interneurons originating in the lateral/caudal ganglionic eminence and preoptic area. PLoS One 8, e77339. Rudy, B., Fishell, G., Lee, S., Hjerling-Leffler, J., 2011. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61. Sheth, A.N., Bhide, P., 1997. Concurrent cellular output from two proliferative populations in the early embryonic mouse corpus striatum. J. Comp. Neurol. 383, 220–230. Somogyi, P., 1977. A specific'axo-axonal' interneuron in the visual cortex of the rat.
Brain Res. 136, 345–350. Sousa, V.H., Miyoshi, G., Hjerling-Leffler, J., Karayannis, T., Fishell, G., 2009. Characterization of Nkx6-2-derived neocortical interneuron lineages. Cereb. Cortex 19 (Suppl 1), i1–10. Southwell, D.G., Nicholas, C.R., Basbaum, A.I., Stryker, M.P., Kriegstein, A.R., Rubenstein, J.L., Alvarez-Buylla, A., 2014. Interneurons from embryonic development to cell-based therapy. Science 344. Tamamaki, N., Fujimori, K.E., Takauji, R., 1997. Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J. Neurosci. 17, 8313–8323. Tamamaki, N., Yanagawa, Y., Tomioka, R., Miyazaki, J., Obata, K., Kaneko, T., 2003. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J. Comp. Neurol. 467, 60–79. Tomishima, M.J., Hadjantonakis, A.K., Gong, S., Studer, L., 2007. Production of green fluorescent protein transgenic embryonic stem cells using the GENSAT bacterial artificial chromosome library. Stem Cells 25, 39–45. Tricoire, L., Pelkey, K.A., Daw, M.I., Sousa, V.H., Miyoshi, G., Jeffries, B., Cauli, B., Fishell, G., McBain, C.J., 2010. Common origins of hippocampal Ivy and nitric oxide synthase expressing neurogliaform cells. J. Neurosci.: Off. J. Soc. Neurosci. 30, 2165–2176. Tyson, J.A., Anderson, S.A., 2014. GABAergic interneuron transplants to study development and treat disease. Trends Neurosci. 37, 169–177. Tyson, J.A., Goldberg, E.M., Maroof, A.M., Petros, T.P., Anderson, S.A., 2015. Duration of culture and Sonic Hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells. Development 142, 1267–1278. Watanabe, K., Kamiya, D., Nishiyama, A., Katayama, T., Nozaki, S., Kawasaki, H., Watanabe, Y., Mizuseki, K., Sasai, Y., 2005. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci. 8, 288–296. Watanabe, K., Ueno, M., Kamiya, D., Nishiyama, A., Matsumura, M., Wataya, T., Takahashi, J.B., Nishikawa, S., Muguruma, K., Sasai, Y., 2007. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol. 25, 681–686. Wonders, C.P., Taylor, L., Welagen, J., Mbata, I.C., Xiang, J.Z., Anderson, S.A., 2008. A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. Dev. Biol. 314, 127–136. Xu, Q., Cobos, I., De La Cruz, E., Rubenstein, J.L., Anderson, S.A., 2004. Origins of cortical interneuron subtypes. J. Neurosci.: Off. J. Soc. Neurosci. 24, 2612–2622. Xu, Q., Guo, L., Moore, H., Waclaw, R.R., Campbell, K., Anderson, S.A., 2010a. Sonic hedgehog signaling confers ventral telencephalic progenitors with distinct cortical interneuron fates. Neuron 65, 328–340. Xu, Q., Tam, M., Anderson, S.A., 2008. Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J. Comp. Neurol. 506, 16–29. Xu, Q., Wonders, C.P., Anderson, S.A., 2005. Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon. Development 132, 4987–4998. Xu, X., Roby, K.D., Callaway, E.M., 2010b. Immunochemical characterization of inhibitory mouse cortical neurons: three chemically distinct classes of inhibitory cells. J. Comp. Neurol. 518, 389–404. Zhao, Y., Flandin, P., Long, J.E., Cuesta, M.D., Westphal, H., Rubenstein, J.L., 2008. Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants. J. Comp. Neurol. 510, 79–99.