From stem cells to neurons and glia: a Soxist's view of neural development

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From stem cells to neurons and glia: a Soxist’s view of neural development Michael Wegner and C. Claus Stolt Institut fu¨r Biochemie, Universita¨t Erlangen-Nu¨rnberg, D-91054 Erlangen, Germany

During nervous system development, neural stem cells give rise to many different types of neurons and glia over an extended period. Little is known about the intrinsic factors that regulate stem-cell maintenance, decide whether neurons or glia are generated, or control terminal differentiation. Transcription factors of the Sox family provide important clues about the control of these events. In the central nervous system (CNS), Sox1, Sox2 and Sox3 are required for stem-cell maintenance, and their effects are counteracted by Sox21. Sox9, by contrast, alters the potential of stem cells from neurogenic to gliogenic, whereas Sox10 is essential for terminal oligodendrocyte differentiation. In the peripheral nervous system (PNS) the same Sox proteins have different functions, uncovering important developmental differences between the CNS and PNS. Introduction The vertebrate nervous system contains many different neuron types that are supported by macroglia such as oligodendrocytes, astrocytes and Schwann cells. Macroglia constitute a heterogeneous population of cells that form myelin sheaths around axons, provide trophic and nutritional support for neurons and maintain extracellular homeostasis at synapses. Additionally, glia serve as a stem-cell reservoir in the adult nervous system. The cellular complexity is further enhanced by differences between the peripheral (PNS) and central (CNS) nervous system. Neurons and macroglia of the CNS arise from selfrenewing pluripotent neuroepithelial progenitors. Most cells of the PNS, by contrast, can be traced back to the neural crest. Several basic helix–loop–helix and homeodomain proteins have been identified as proneural or neurogenic transcription factors involved in neuronal specification and early determination events [1,2], but the transcriptional control of many other phases of neural development, including stem-cell maintenance, glial specification and lineage-specific terminal differentiation, are poorly understood. This is where Sox proteins come into play. Members of this group of transcription factors are characterized by a high-mobility-group DNA-binding domain that was first identified in the mammalian Sry protein [3–5]. There are 20 different Sox proteins in mammals and eight in Drosophila melanogaster [3,6]. Usually, several vertebrate paralogs exist for an invertebrate Sox protein, and these Corresponding author: Wegner, M. ([email protected]). Available online 31 August 2005

paralogs make up a common Sox group. The importance of Sox proteins for nervous system development has long been assumed from their expression patterns [7,8], but has only recently been proven in loss-of-function and gainof-function studies. Although best known for its essential role during male sex determination in mammals, even the prototypic family member Sry is strongly expressed in the mammalian brain and could be involved in its male-specific differentiation [9]. SoxB1 proteins convey neuroectodermal competence The presumptive vertebrate neuroectoderm already expresses Sox proteins such as Sox2 [10–12]. Ectopic expression in Xenopus laevis indicates that Sox2 is essential for neuroectoderm formation and functions as a neural competence factor [11]. Similarly, stable Sox2 expression in embryonic stem cells does not interfere with self-renewal under proliferative conditions, but forces cells to develop into neuroectodermal derivatives upon release from self-renewal [13]. Forced expression of the closely related Sox1 in embryonic stem or carcinoma cells leads to comparable effects [13,14], arguing that Sox1 and Sox2 have equivalent functions. This conclusion can be extended to Sox3, which together with Sox1 and Sox2 makes up the SoxB1 group. In the early neuroectoderm, SoxB1 proteins are expressed in a strongly overlapping manner [12,15,16]. Because of their biochemical and functional similarities, SoxB1 proteins exhibit redundancy and compensate for the loss of each other, so that formation and development of the neuroectoderm is normal in Sox1-deficient and Sox3-deficient mice, and in Sox2 hypomorphs [17–19]. In fact, coexpression of highly related Sox proteins is a recurrent theme during nervous system development. The resulting redundancy often masks the function of a particular Sox protein in loss-of-function studies. Stem-cell maintenance in the CNS requires the proper balance of SoxB1 and SoxB2 proteins All SoxB1 proteins continue to be expressed in selfrenewing neuroepithelial progenitors throughout CNS development. As recently reviewed [15], gain-of-function experiments using in ovo electroporation of the chicken neural tube have yielded important insights into the early CNS function of SoxB1 proteins [20,21]. Forced expression of Sox1, Sox2 or Sox3 maintains a stem-cell-like state and actively inhibits neuronal differentiation, whereas inhibition of their activity leads to premature cell-cycle exit

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Figure 1. SoxB proteins in early CNS development. (a) In the wild-type vertebrate neural tube, Sox2 is expressed in all pluripotent self-renewing progenitors of the ventricular zone (light green). After unilateral electroporation of the chick neural tube with additional Sox2 (dark green), neuroepithelial progenitors fail to undergo neuronal specification on the electroporated side, so regions lateral to the ventricular zone contain fewer differentiated cells than normal. Electroporation of Sox21 inhibits function of all SoxB1 proteins, and premature neuronal differentiation is accompanied by a depletion of neuroepithelial progenitors (red) on the electroporated side. (b) In Drosophila, SoxNeuro (red) and Dichaete (green) are expressed in an overlapping pattern (yellow) in the neuroectoderm (NE) and the resulting neuroblasts (NB). SoxB expression in neuroblasts is not represented in this figure. In a SoxNeuro mutant, lateral neuroblasts (lNB) and intermediate neuroblasts (iNB) are lost, whereas only midline glia (MG) are abolished in the Dichaete mutant. Severe effects on medial neuroblasts (mNB) require simultaneous inactivation of both SoxNeuro and Dichaete in the double mutant.

and initiates neuronal differentiation (Figure 1a). Key to their negative effect on neuronal differentiation is the ability of SoxB1 proteins to counteract coexpressed proneural proteins. It could be that Sox proteins sequester proneural proteins in complexes, where the proneural proteins lose the ability to bind to DNA or to transactivate. Proneural proteins reciprocally suppress expression and activity of SoxB1 proteins in neural precursors. One mechanism through which proneural proteins counteract the activity of SoxB1 proteins involves upregulation of Sox21 [22], which strongly overlaps in expression with SoxB1 proteins [8]. Sox21 and Sox14 together make up the SoxB2 group of transcription factors [3], which are closely related to SoxB1 proteins and probably bind to the same target sequences, but possess a repression domain instead of a C-terminal transactivation domain [23]. They specifically interfere with SoxB1-dependent activation [23] and as a consequence promote progression of neurogenesis in the developing CNS [22] (Figure 1a). The decision of a neural precursor to self-renew or to undergo neuronal differentiation therefore depends on the balance of SoxB1 and SoxB2 proteins. By inducing Sox21 expression, proneural proteins influence this balance and inhibit SoxB1 activity [22]. www.sciencedirect.com

SoxB1 proteins continue to be expressed and to function in adult neural stem cells. Sox2, in particular, is strongly expressed in the subventricular zone of the lateral ventricles and in the subgranular layer of the hippocampal dentate gyrus. Upon reduced Sox2 expression in a hypomorphic mouse mutant, profound defects in adult neurogenesis are observed in both regions [18]. SoxB function in CNS development is evolutionarily conserved Two SoxB proteins are strongly expressed in the developing Drosophila neuroectoderm in a partially overlapping pattern (Figure 1b). SoxNeuro occurs in all regions of the neuroectoderm, whereas Dichaete (also known as Fish-hook) is found primarily in the medial neuroectoderm and absent from the lateral neuroectoderm [24,25]. Both act during neuroectoderm specification and neuroblast formation. After SoxNeuro inactivation, neuroblasts are severely reduced in the lateral and intermediate regions of the neuroectoderm, whereas significant loss of correctly specified neuroblasts in the medial region requires concomitant deletion of both SoxNeuro and Dichaete [24,26]. In Drosophila, there is little evidence for the antagonistic role of SoxB1 and SoxB2 proteins found in vertebrates. Whereas SoxNeuro is a SoxB1 protein, Dichaete is more closely related to the SoxB2 group [3]. Genetically, both Drosophila SoxB proteins function upstream of and in parallel to the proneural genes of the Achaete–Scute complex and cooperate with Gsh-type, Nkx-type and POU-type homeodomain transcription factors [26–29]. Functional redundancy of Drosophila SoxB proteins and interaction with proneural proteins are not the only similarities with SoxB1 action in early vertebrate CNS development. There is also significant coexpression of SoxB1 proteins in the vertebrate nervous system with orthologs of the Drosophila Gsh-type, Nkx-type and POU-type homeodomain transcription factors [30,31]. Analysis of nestin expression in neural stem cells, for instance, highlights the cooperation between Sox proteins and POU-type homeodomain transcription factors because the nestin stem-cell enhancer is jointly regulated by SoxB1 proteins and Brn-2 [31]. Outside the nervous system, cooperative interactions with other transcription factors are a general requirement for the function of Sox proteins [5,32]. Only in combination can Sox proteins and their interaction partners activate transcription by efficiently establishing contacts with the basic transcription machinery, with transcriptional co-activators, with chromatin modifiers or with chromatinremodeling complexes [33]. In many regulatory regions outside the nervous system, and in the nestin enhancer, these transcription factors bind to recognition elements immediately adjacent to those of Sox proteins [31,32]. Nevertheless, it is also possible that Sox proteins bind to regulatory regions considerable distances from their partner proteins. In contrast to most other DNA-binding proteins, Sox proteins interact with the minor groove and introduce strong bends into DNA [4]. Consequently, Sox proteins could act as architectural proteins, to shape gene regulatory regions into defined 3D conformations that

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should enable them to establish physical contacts with transcription factors bound far apart on the same target gene promoter or enhancer [32].

SoxE proteins are required for CNS gliogenesis Slightly preceding the onset of gliogenesis, neuroepithelial cells in the mouse spinal cord start to express Sox9 and Sox8 in the continued presence of SoxB1 proteins [34] (Figure 2a). Compared with Sox9, Sox8 is expressed in lower amounts and with a slight temporal delay [35]. These two Sox proteins and Sox10 make up the SoxE group in vertebrates. In contrast to SoxB1 proteins, presence of SoxE proteins is not essential for survival or self-renewal of neuroepithelial progenitors [34,35], indicating that functional redundancy between less closely related Sox proteins from different groups is probably limited. Sox9 deletion in the developing mouse spinal cord instead interferes with glial specification and consequently decreases both (a)

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Figure 2. SoxE proteins in embryonic vertebrate CNS development. (a) Pluripotent neuroepithelial progenitors in the ventricular zone of the mouse spinal cord start to express Sox9 (red) w10.5 days post coitum (dpc). At 13.5 dpc, Sox9 is additionally present in astrocyte (triangles) and oligodendrocyte (ellipses) progenitors but not in motoneurons (rectangles). Oligodendrocyte progenitors also express Sox10 (green). Whereas Sox9 continues to be expressed at 18.5 dpc in astrocytes, it is lost from oligodendrocytes that undergo terminal differentiation in the marginal zone of the spinal cord (stars). (b) Generation of oligodendrocytes and astrocytes is severely impaired at 13.5 dpc in Sox9-deficient mouse spinal cord because of a specification defect. Neuronal populations are reciprocally increased, as shown for motoneurons. (c) Terminal differentiation of oligodendrocyte precursors is not initiated in the marginal zone of the Sox10-deficient mouse spinal cord. www.sciencedirect.com

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oligodendrocytic and astrocytic populations [34]. Additional loss of Sox8 enhances the oligodendrocytic defect [35]. The absence of Sox9 not only decreases macroglia numbers but concomitantly increases the generation of various neuronal subtypes. Thus, motoneurons are still born in significant numbers from the pMN domain of the ventral spinal cord at a time when this domain should have started to produce primarily oligodendrocytes (Figure 2b). It is tempting to assume that Sox9 (supported by Sox8) changes the competence of neuroepithelial progenitors in the spinal cord and enables them to generate macroglial lineages. Sox9 is thus the first example of a transcription factor involved in altering the potential of a CNS stem cell from neurogenic to gliogenic. SoxE proteins are required for terminal differentiation of CNS macroglia Whereas SoxB1 expression is extinguished rapidly in most neuronal precursors [20,21], the SoxE proteins Sox8 and Sox9 continue to be widely expressed even after the initial specification event in both astrocytic and oligodendrocytic lineages [34,36]. After specification, oligodendrocyte progenitors in the spinal cord also upregulate Sox10 [37] (Figure 2a). During the following oligodendrocyte progenitor proliferation and colonization of the spinal cord, SoxE proteins function redundantly, similar to SoxB1 proteins in the self-renewing neuroepithelial progenitors. However, Sox9 disappears from the oligodendrocyte lineage with the onset of terminal differentiation [34,37] (Figure 2a). Despite continued expression of low amounts of Sox8 [36], loss of Sox10 can no longer be compensated for, so terminal differentiation of oligodendrocytes and myelination are severely inhibited in the Sox10-deficient spinal cord [37] (Figure 2c). Sox10 controls the expression of several myelin genes, including those encoding myelin basic protein (MBP) and proteolipid protein. At least for MBP, the regulation appears to be direct because the proximal MBP promoter is bound and activated by Sox10 [37]. The partner protein for Sox10 in this regulation has not yet been identified. Altered myelin gene expression is a likely reason for dysmyelinating CNS leukodystrophy in some human patients with heterozygous SOX10 mutations [38]. There also is a SoxE protein in Drosophila (Sox100B) [39]. However, Sox100B is not involved in glial specification (like Sox9) or in terminal differentiation of glia (like Sox10). In fact, Sox100B is not expressed in the fly nervous system, and deletion of Sox100B does not cause an obvious phenotype [39]. In striking contrast to SoxB proteins, there is no evidence for an evolutionarily conserved function of SoxE proteins in nervous system development. SoxB1 proteins have late subtype-specific functions in postmitotic neurons SoxE transcription factors are not the only Sox proteins that continue to be present in postmitotic cells of the adult CNS. Whereas Sox10 maintains the phenotype of differentiated oligodendrocytes, SoxB1 proteins have been detected in select sets of differentiated neurons. In the adult brain, Sox2 is, for instance, expressed not only in adult neural stem cells but also in subtypes of postmitotic

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neurons, including pyramidal cells of the cerebral cortex, some striatal neurons and many thalamic neurons [18]. Accordingly, mice with strongly reduced Sox2 levels show signs of neurodegeneration in areas where Sox2 is expressed in mature neurons, and they display corresponding neurological abnormalities. Neurological symptoms in human anophthalmia patients with heterozygous SOX2 mutations are also consistent with Sox2 functioning in mature neurons [40,41]. Expression of SoxB1 proteins overlaps much less in the mature brain than during embryonic CNS development. Sox1 expression is particularly strong in GABAergic neurons of the ventral striatum. In Sox1-deficient mice, focal neuroanatomical abnormalities in several structures of the ventral striatum, including the olfactory tubercle, the islands of Calleja and the shell of the nucleus accumbens, are caused by specific defects in postmitotic neurons, which in the absence of Sox1 fail to migrate to their proper location and fail to differentiate [30]. This defect secondarily disrupts local neuronal circuits and results in seizures [42]. Sox3, by contrast, is preferentially expressed in mature neurons of the ventral hypothalamus [19]. Loss of Sox3 correspondingly compromises number, activity and/or connectivity of growth-hormone-releasing hormone (GHrH)-positive hypothalamic neurons, thus contributing to the hypopituitarism and mental retardation observed in Sox3-deficient mice and in human patients with SOX3 mutations [19,43]. In accord with the evolutionary conserved role, Drosophila SoxB proteins are also expressed in distinct subsets of mature neurons [44]. Sox proteins control different stages of PNS development It is not possible to infer PNS functions from the CNS function of a Sox protein. Thus, SoxB1 transcription factors are not essential in early PNS development from the neural crest and they have only minor roles in late phases. Sox2, for instance, is transiently expressed in the Schwann cell lineage at the precursor and immature Schwann cell stages (Figure 3b) and prevents terminal differentiation [45]. SoxB1 proteins even appear incompatible with neuralcrest formation, because forced Sox2 expression in the prospective neural crest leads to neuroectoderm expansion and neural-crest loss [46]. Instead, the emerging vertebrate neural crest prominently expresses SoxE proteins [47–53]. Accordingly, their forced expression causes cells of the early chick neural tube to acquire neural-crest characteristics [49]. Thus, not only are SoxE and SoxB1 proteins reciprocally expressed in the selfrenewing stem-cell populations of PNS and CNS, but their presence also has opposite effects on the chosen cell fate. Among SoxE proteins, Sox9 generally appears before Sox10 in the premigratory neural crest (Figure 3a), although regional and species-specific differences exist. In the mouse, deletion of both Sox9 and Sox10 affects development of neural-crest stem cells, with Sox9 effects more severe in the trunk and Sox10 effects particularly visible in the vagal region [54,55]. The enteric nervous system, as one main derivative of the vagal neural crest, is www.sciencedirect.com

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Figure 3. Sox proteins in embryonic vertebrate PNS development. (a) In the premigratory neural crest of the trunk, Sox9 (red) is turned on before Sox10 (green). Neural crest stem cells (ellipses) migrating along the ventral and dorsolateral (i.e. melanocyte-generating) pathway turn-off Sox9 expression, but continue to express Sox10. In the absence of Sox9, many premigratory neural crest cells undergo apoptosis. (b) Once neural crest cells on the ventral pathway have reached their destination, they become specified into neurons (circles), which lose Sox10 expression, or glia (squares), which continue to express Sox10. Schwann cell precursors along nerves additionally turn on Sox2 (yellow). In the absence of Sox10, no glia are generated. Ganglia are hypoplastic and neurons are found at ectopic positions along nerves. Abbreviations: DRG, dorsal root ganglion; NC, notochord; NT, neural tube; Sym, sympathetic ganglion. Panels correspond to w9.5 dpc and w12.5 dpc of mouse embryogenesis, respectively.

strongly affected by loss or inactivation of one Sox10 allele in mice [56,57], leading to aganglionosis of the distal colon. This, in combination with melanocyte defects, is the hallmark of mouse Sox10 mutations and is also observed in most humans with SOX10 mutations who suffer from Waardenburg–Hirschsprung disease [58]. In the premigratory neural crest, SoxE proteins are important for stem-cell survival and additionally provide competence for the epithelial–mesenchymal transition [55]. As is typical for Sox proteins, they do not act alone, but act coordinately with FoxD3, Slug/Snail proteins and establish a self-reinforcing cross-regulatory transcriptional network. Whereas expression of Sox9 is transient in most neural-crest regions, Sox10 expression continues in migrating neural-crest stem cells, where it ensures stem-cell survival, maintains pluripotency and suppresses neuronal differentiation [59]. When neural-crest cells

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have reached their final destination and become postmigratory in the developing PNS, Sox10 follows one of two fates. In cells determined to a neuronal fate, Sox10 is turned off (Figure 3b) after a transient phase of coexpression with proneural genes [59]. In cells determined to a glial fate, Sox10 remains expressed, independent of whether these glia develop in ganglia as satellite cells, along nerves as Schwann cells or in an intestinal plexus as enteric glia [51,60] (Figure 3b). Sox10 is in fact required for specification of all PNS glia, as evident from their complete absence in Sox10-deficient mice (Figure 3b). Without glia, neurons are generated in peripheral ganglia and are found at ectopic positions along nerves, but eventually disappear owing to the lack of trophic glial support. Persistent Sox10 expression in PNS glia points to further roles after the original specification event. Krox-20, which regulates many aspects of Schwann cell myelination, appears to be under control of Sox10 [61]. Additionally, expression of several peripheral myelin genes such as Connexin-32 and Myelin protein zero is directly induced by Sox10 [62,63]. In the case of Connexin-32, Krox-20 has been identified as the partner protein for Sox10 [62]. Supporting the role of Sox10 in peripheral myelination, mutation of the Sox10-binding site within the Connexin-32 promoter leads to Charcot– Marie–Tooth type 1 peripheral neuropathy [62]. Comparable peripheral neuropathies in patients with heterozygous SOX10 mutations [38] might thus be due not only to disturbed Schwann cell development but also to dysregulated myelin gene expression. Myelin genes are targets for Sox10 only in differentiating and differentiated glia. Thus, Sox10 must act through different target genes, at early times when it is important for stem-cell maintenance and glial specification. Conclusions and perspectives During nervous system development, a particular Sox protein can be involved in many different processes, including maintenance of pluripotency in self-renewing stem cells, specification events, lineage progression and terminal differentiation. Sox proteins thus are inherently flexible pleiotropic regulators that function in a contextdependent manner. Part of this functional flexibility is provided by a strict requirement for transcriptional partner proteins. A few of these partner proteins have been identified so far during nervous system development, including Brn-2 for SoxB1 proteins in CNS stem cells [31] and Krox-20 for Sox10 in differentiating Schwann cells [62]. It will be a major challenge in the coming years to identify the transcription factors with which Sox proteins interact in the developing nervous system. This will also be helpful in unraveling and comparing the transcriptional programs jointly controlled by Sox proteins and their partners during consecutive phases of cell-lineage progression and during CNS versus PNS development. Although this review has focused on SoxB and SoxE proteins, expression studies indicate that several other Sox transcription factors are also present in the developing nervous system. Group C members Sox4 and Sox11 are for instance jointly expressed in cells that are already specified but not yet differentiated. Although www.sciencedirect.com

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they are believed to influence neural lineage progression and maturation, supporting evidence has been difficult to obtain in loss-of-function studies because these two Sox proteins exhibit a near identical expression pattern and are likely to be functionally redundant [64,65]. Furthermore, there is emerging evidence for participation of SoxD proteins in early neural crest and PNS development [66], and in neuroectodermal differentiation [67]. Future studies will need to clarify the role of these additional Sox proteins during nervous system development, and also address whether and how coexpressed, more distantly related Sox proteins modulate activity of one another. The opposing activity of SoxB1 and SoxB2 proteins in CNS stem cells [22] is not the only evidence for the existence of a cross-talk between different Sox groups. SoxE proteins, for instance, interact with SoxD proteins in chondrocyte development [68]. Therefore, a complex interplay between different Sox proteins is expected, and this could be as important as interactions with non-Sox partners for the role of Sox proteins during neural development. Acknowledgements Research on Sox proteins in the Wegner laboratory is supported by grants from DFG, Thyssen-Stiftung, Schram-Stiftung and Fonds der Chemischen Industrie.

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