- Email: [email protected]
Population Control: Cortical Interneurons Modulate Oligodendrogenesis
Neuron
Previews Population Control: Cortical Interneurons Modulate Oligodendrogenesis Pratiti Bandopadhayay1 and Charles D. Stiles2,* 1Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA 2Department of Neurobiology, Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA 02115, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2017.04.032
During central nervous system development, oligodendrocytes must be formed in proportion to the number of neurons requiring their services. In this issue of Neuron, Voronova et al. (2017) show how cortical interneurons modulate oligodendrogenesis through a cytokine-mediated paracrine interaction. Proportionality between myelinating cells and neurons is required in both the peripheral and the central nervous systems. However, population control is simpler within the peripheral nervous system, where each Schwann cell enwraps only a single axon and the axons themselves provide neuregulin—a key Schwann cell mitogen (Salzer, 2015). By contrast, in the central nervous system, a single myelinating oligodendrocyte may contact and enwrap 40–50 axons. Importantly, axonal contact, enwrapment, and myelination occur at relatively late stages of central nervous system development. How do emerging neurons inform oligodendrocyte progenitors as to their numbers and future needs for enwrapment? In this issue of Neuron, Voronova et al. (2017) address this question in an elegant series of studies with practical overtones for neurologic disease states, including CNS cancers. The point of departure for their studies is a cellular ‘‘traffic jam’’ in the developing neocortex. As depicted in Figure 1, beginning at around E12.5, GABAergic interneuron progenitors born in the medial and lateral ganglionic eminences (MGE and LGE, respectively) begin their tangential migration toward the presumptive neocortex (Yokota et al., 2007). At the same time, a burst of oligodendrocyte progenitors born in the MGE begins a similar trek to the neocortex. This initial population of oligodendrocyte progenitors is followed by a second wave of progenitors born in the LGE and a third cohort born in the neocortex itself (Kessaris et al., 2006). At E15, GABAergic interneurons can already be seen interacting with radial
glia projection filaments in upper layers of the developing cortex, but some are also found in the ventricular and subventricular zones, where they mingle with the Pax6positive radial glia precursors. By P0, the presumptive corpus callosum is well populated by oligodendrocyte progenitor cells marked by the bHLH transcription factor Olig2 as well as the platelet-derived growth factor a receptor (PDGFRa). Against this anatomical backdrop, Voronova et al. (2017) elegantly dissect the contribution of interneurons in signaling cortical precursor cells to proliferate and differentiate into cortical oligodendrocytes. First, using in vitro co-culture assays, the authors demonstrate that interneurons generated from the MGE (E13) initially enhance proliferation of cortical precursor cells and, at a later time, increase oligodendroglial (but not astrocytic) differentiation. Importantly, they show that this is a consequence of secreted factors rather than direct cellcell contact. Conditioned media collected from cultures of MGE interneurons was sufficient to increase populations of both Sox2-positive precursor cells, which can generate both oligodendrocytes and astrocytes, and MBP-positive, differentiated oligodendrocytes. The cell culture findings were validated in vivo, using a mouse engineered to carry an Nkx2.1-Cre transgene and a YFP reporter gene with an upstream floxed stop cassette in the Rosa26 locus. In this system, progeny of MGE precursors are labeled with a YFP tag. The authors confirmed arrival of MGE-derived interneurons within the cortex of E15 mice, with cells also detected in the subventric-
ular zone, ventricular zone, intermediate zone, and cortical plate (see Figure 1). They next leveraged this system using intercrosses of their Nkx2.1-Cre driver mice with floxed diphtheria toxin receiver mice. Ablation of MGE-derived interneurons in these intercross animals resulted in a reduction of oligodendrocyte progenitors marked by expression of Olig2 and PDGFRa. Thus, MGE-derived interneurons have the ability to expand the number of precursor cells and drive oligodendrocyte formation in culture—and they are required to do so during normal development. To identify interneuron-derived signaling factors, the authors interrogated mRNA microanalysis from isolates of cultured MGE interneurons and cortical progenitors. Their in silico screen initially presented 53 candidate ligand-receptor pairs. Three of these looked especially promising, and follow-up studies in cell culture converged upon the secreted factor fractalkine (Cx3cl1) and its receptor (Cx3cr1). Addition of fractalkine to the culture media of E13 cortical precursors was sufficient to increase the proportion of oligodendrocytes, and this effect was blocked in the presence of antibodies directed toward Cx3cr1. Increased proportions of oligodendrocytic cells (defined by markers such as PDGFRa and, ultimately, myelin itself) could in principle be achieved through an expansion of the population of multipotent precursor cells, specification of these precursors toward the oligodendrocyte lineage, enhanced oligodendrocytic differentiation, or survival. Labeling experiments with BrdU showed that fractalkine did not
Neuron 94, May 3, 2017 ª 2017 Elsevier Inc. 415
Neuron
Previews
affect proliferation. Likewise, cell development beginning at E13/ survival, as marked by E14 when these cells first arrive condensed apoptotic nuclei, at the germinal layers of the prewas unperturbed. However, the sumptive cortex and extending authors did observe an increase to at least during the first few in the relative proportion of weeks of postnatal life. A key PDGFRa-positive oligodendroMGE-derived ligand is the checyte cells within the cultures, mokine fractalkine, which, via its suggesting that fractalkine funccognate receptor Cx3cr1, protions to increase the differentiamotes maturation of oligodention of committed oligodendrodrocyte progenitors. It must be cyte progenitors. Importantly, noted (and the authors concede) the authors demonstrated that that fractalkine does not have fractalkine can stimulate oligoan exclusive license to practice dendrocytic differentiation of oligodendrocyte population conboth embryonic and postnatal trol. In particular, MGE-derived oligodendrocyte precursors. interneurons appear to promote Turning again to animal mitosis of cortical progenitors in models, the authors found that culture and in animals (Figures 1 MGE-derived interneurons exand 2, respectively, in Voronova press fractalkine mRNA at E17 et al., 2017), whereas fractalwithin the germinal zones and kine’s effects are confined to difcortical plate. By P4, fractalkine ferentiation. Gas6 was identified mRNA expression is robust as another potential interthroughout the cortical mantle. neuron-secreted ligand by the Likewise, by E17, Sox2-positive authors’ in silico screen, and the progenitors in the ventricular interneuron transmitter GABA itand subventricular zones co-exself has been shown to impact press Olig2 and Cx3cr1 mRNA. oligodendrocyte biology (see Co-expression of Sox2, Olig2, Voronova et al. and references and Cx3cr1 is sustained through therein). PDGF is also expressed P4 in cells within and immediin neurons, and a broad body ately basal to the subventricuof data highlights a role for lar zone. PDGF in oligodendrogenesis, The authors were also able to for example (Calver et al., Figure 1. Anatomical Backdrop to Voronova et al. confirm a role for Cx3cr1 in 1998). Curiously, none of these (Bottom panel) A traffic jam in the developing neocortex: coronal neuron-derived factors seem to cortical oligodendrogenesis by section of E12.5 telencephalon, adapted from Kessaris et al. (2006) and Yokota et al. (2007). Beginning at E12.5, interneurons born in the meet the needs of the first wave showing that Cx3cr1 null mice MGE and (to a somewhat lesser extent) in the LGE begin radial of oligodendrocyte progenitors exhibit a reduction in the propormigration toward the neocortex. At the same time, the first of three born in the MGE that arrive in tion of cortical Olig2-positive waves of oligodendrocyte progenitors is born in the MGE and begins migration ventrally and also dorsally toward the neocortex. A second the presumptive cortex at around cells. A worry with the Cx3cr1 burst of oligodendrocyte progenitors derived from the LGE will begin E16. By P10, the majority of these null mouse model was that other migration a few days later. A third wave of progenitors will be born MGE-derived oligodendrocyte cell types (notably microglia) locally within the cortex beginning at around P0. (Middle panel) The state of affairs at E15 (from Voronova et al., 2017): MGE-derived inprogenitors have been cleared express the receptor. Accordterneurons have arrived in the neocortex, where they intermingle with from the cortex and corpus calingly, the observed effects on Pax6-positive radial precursor cells within the germinal layers and also losum to be replaced by progenOlig2-positive cell types might with nestin-positive processes from these cells in the upper cortical itors derived from the LGE and be non-cell autonomous. To layers. The first wave of MGE-derived oligodendrocyte progenitors will arrive a day or so later (Kessaris et al., 2006). (Top panel) The P0 cortex also locally born progenitors address this concern, the (from Voronova et al., 2017): MGE-derived interneurons in close (see Figure 1 and also Kessaris authors electroporated Cx3cr1 proximity to oligodendrocyte progenitors in the apical cortex. At this et al., 2006). shRNAs in the PB transposon stage, most of the MGE-derived oligodendrocyte progenitors have already been eliminated, so these progenitors are derived from the Are there any practical oversystem into the cortex of LGE or born locally (Kessaris et al., 2006). tones to the fractalkine:Cx3cr1 E14 mouse embryos. These signaling axis? Studies with mufocused knockdown experirine models of multiple sclerosis ments confirmed that suppression of Cx3cr1 selectively reduced the Collectively, the studies of Voronova (MS) have shown that Cx3cr1 null mice abundance of oligodendrocyte lineage et al. (2017) define a role for MGE-derived exhibit aberrant recruitment of Olig2/ cells and that microglia were not targeted interneurons in modulation of oligoden- PDGFRa-positive oligodendrocyte proby the electroporation protocol. drocyte formation at multiple stages of genitor cells into regions of demyelination 416 Neuron 94, May 3, 2017
Neuron
Previews induced by cuprizone or experimental autoimmune encephalomyelitis (Garcia et al., 2013; Lampron et al., 2015). Microglia express Cx3cr1, and these prior studies focused on defective microglia as the underlying cause of the remyelination phenotype. However, the observations of Voronova et al. (2017) suggest that the biologically relevant target of Cx3cr1 ablation in these MS models may be the oligodendrocyte precursors or progenitors. On another disease front, oligodendrocyte progenitors are an attractive ‘‘cellof-origin’’ candidate for malignant glioma, and neuron-derived factors are an emerging area of focus for these tumors. One recent study highlights a link between neuronal activity and glioma growth through secretion of neuroligin-3 (Venkatesh et al., 2015). However, the work of Voronova et al. (2017) suggests that neuron-derived fractalkine might work in opposition to glioma growth. The Olig2 transcription factor—essential to forma-
tion of oligodendrocyte progenitors—is likewise essential for maintaining ‘‘stemness’’ and tumorigenic potential of patient-derived glioma cell lines (Suva` et al., 2014). Olig2 also happens to associate with the Cx3cr1 gene in postnatal oligodendrocyte progenitors (Yu et al., 2013). The authors suggest that fractalkine might oppose glioma growth by promoting differentiation of Olig2-positive tumor initiating cells further down the oligodendrocyte lineage. Those of us who battle these tumors at the bench and at the bedside would look forward with great interest to a test of this hypothesis.
Kessaris, N., Fogarty, M., Iannarelli, P., Grist, M., Wegner, M., and Richardson, W.D. (2006). Nat. Neurosci. 9, 173–179. Lampron, A., Larochelle, A., Laflamme, N., Pre´fontaine, P., Plante, M.-M., Sa´nchez, M.G., Yong, V.W., Stys, P.K., Tremblay, M.-E`., and Rivest, S. (2015). J. Exp. Med. 212, 481–495. Salzer, J.L. (2015). Cold Spring Harb. Perspect. Biol. 7, a020529. Suva`, M.L., Rheinbay, E., Gillespie, S.M., Patel, A.P., Wakimoto, H., Rabkin, S.D., Riggi, N., Chi, A.S., Cahill, D.P., Nahed, B.V., et al. (2014). Cell 157, 580–594. Venkatesh, H.S., Johung, T.B., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E.M., Mount, C.W., Polepalli, J., Mitra, S.S., et al. (2015). Cell 161, 803–816. Voronova, A., Yuzwa, S.A., Wang, B., Zahr, S., Syal, C., Wang, J., Kaplan, D.R., and Miller, F.D. (2017). Neuron 94, this issue, 500–516.
REFERENCES Calver, A.R., Hall, A.C., Yu, W.P., Walsh, F.S., Heath, J.K., Betsholtz, C., and Richardson, W.D. (1998). Neuron 20, 869–882. Garcia, J.A., Pino, P.A., Mizutani, M., Cardona, S.M., Charo, I.F., Ransohoff, R.M., Forsthuber, T.G., and Cardona, A.E. (2013). J. Immunol. 191, 1063–1072.
Yokota, Y., Gashghaei, H.T., Han, C., Watson, H., Campbell, K.J., and Anton, E.S. (2007). PLoS ONE 2, e794. Yu, Y., Chen, Y., Kim, B., Wang, H., Zhao, C., He, X., Liu, L., Liu, W., Wu, L.M.N., Mao, M., et al. (2013). Cell 152, 248–261.
Lethal Giant Lineage Tracing: Mutating Locally, Acting Globally Aslam Abbasi Akhtar,1,2 Hannah Park,1,2 and Joshua J. Breunig1,2,3,4,* 1Board
of Governors Regenerative Medicine Institute of Biomedical Sciences 3Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 4Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2017.04.030 2Department
The generation of neurons and glia from radial glia progenitors is critical to proper neocortical development but the mechanisms regulating their deterministic production are unclear. In this issue of Neuron, Beattie et al. (2017) use elegant MADM-based lineage tracing to demonstrate cell-intrinsic and global functions for Lgl1 during neocortical development.
Radial glia progenitors (RGPs) are the principal neural precursor type in the developing neocortex, residing in the continuum of neural stem cell types between early neuroepithelial cells and postnatal neural stem cells (Breunig et al., 2011). As such, RGPs are responsible for gener-
ating the diversity of neural types in the forebrain, including neurons, glia, ependymal cells, and persistent neural progenitor populations. Previous work has shown a deterministic pattern of cellular output from individual RGPs in terms of neuron generation (8–9 per RGP) and
gliogenic potential (1 in 6 RGP eventually generating glia) (Gao et al., 2014). Though this seminal work provided insight into the intrinsic potential of individual RGPs, the mechanisms leading to the robust generation of appropriate daughter cell types remain incompletely understood.
Neuron 94, May 3, 2017 ª 2017 Elsevier Inc. 417
Previews Population Control: Cortical Interneurons Modulate Oligodendrogenesis Pratiti Bandopadhayay1 and Charles D. Stiles2,* 1Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA 2Department of Neurobiology, Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA 02115, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2017.04.032
During central nervous system development, oligodendrocytes must be formed in proportion to the number of neurons requiring their services. In this issue of Neuron, Voronova et al. (2017) show how cortical interneurons modulate oligodendrogenesis through a cytokine-mediated paracrine interaction. Proportionality between myelinating cells and neurons is required in both the peripheral and the central nervous systems. However, population control is simpler within the peripheral nervous system, where each Schwann cell enwraps only a single axon and the axons themselves provide neuregulin—a key Schwann cell mitogen (Salzer, 2015). By contrast, in the central nervous system, a single myelinating oligodendrocyte may contact and enwrap 40–50 axons. Importantly, axonal contact, enwrapment, and myelination occur at relatively late stages of central nervous system development. How do emerging neurons inform oligodendrocyte progenitors as to their numbers and future needs for enwrapment? In this issue of Neuron, Voronova et al. (2017) address this question in an elegant series of studies with practical overtones for neurologic disease states, including CNS cancers. The point of departure for their studies is a cellular ‘‘traffic jam’’ in the developing neocortex. As depicted in Figure 1, beginning at around E12.5, GABAergic interneuron progenitors born in the medial and lateral ganglionic eminences (MGE and LGE, respectively) begin their tangential migration toward the presumptive neocortex (Yokota et al., 2007). At the same time, a burst of oligodendrocyte progenitors born in the MGE begins a similar trek to the neocortex. This initial population of oligodendrocyte progenitors is followed by a second wave of progenitors born in the LGE and a third cohort born in the neocortex itself (Kessaris et al., 2006). At E15, GABAergic interneurons can already be seen interacting with radial
glia projection filaments in upper layers of the developing cortex, but some are also found in the ventricular and subventricular zones, where they mingle with the Pax6positive radial glia precursors. By P0, the presumptive corpus callosum is well populated by oligodendrocyte progenitor cells marked by the bHLH transcription factor Olig2 as well as the platelet-derived growth factor a receptor (PDGFRa). Against this anatomical backdrop, Voronova et al. (2017) elegantly dissect the contribution of interneurons in signaling cortical precursor cells to proliferate and differentiate into cortical oligodendrocytes. First, using in vitro co-culture assays, the authors demonstrate that interneurons generated from the MGE (E13) initially enhance proliferation of cortical precursor cells and, at a later time, increase oligodendroglial (but not astrocytic) differentiation. Importantly, they show that this is a consequence of secreted factors rather than direct cellcell contact. Conditioned media collected from cultures of MGE interneurons was sufficient to increase populations of both Sox2-positive precursor cells, which can generate both oligodendrocytes and astrocytes, and MBP-positive, differentiated oligodendrocytes. The cell culture findings were validated in vivo, using a mouse engineered to carry an Nkx2.1-Cre transgene and a YFP reporter gene with an upstream floxed stop cassette in the Rosa26 locus. In this system, progeny of MGE precursors are labeled with a YFP tag. The authors confirmed arrival of MGE-derived interneurons within the cortex of E15 mice, with cells also detected in the subventric-
ular zone, ventricular zone, intermediate zone, and cortical plate (see Figure 1). They next leveraged this system using intercrosses of their Nkx2.1-Cre driver mice with floxed diphtheria toxin receiver mice. Ablation of MGE-derived interneurons in these intercross animals resulted in a reduction of oligodendrocyte progenitors marked by expression of Olig2 and PDGFRa. Thus, MGE-derived interneurons have the ability to expand the number of precursor cells and drive oligodendrocyte formation in culture—and they are required to do so during normal development. To identify interneuron-derived signaling factors, the authors interrogated mRNA microanalysis from isolates of cultured MGE interneurons and cortical progenitors. Their in silico screen initially presented 53 candidate ligand-receptor pairs. Three of these looked especially promising, and follow-up studies in cell culture converged upon the secreted factor fractalkine (Cx3cl1) and its receptor (Cx3cr1). Addition of fractalkine to the culture media of E13 cortical precursors was sufficient to increase the proportion of oligodendrocytes, and this effect was blocked in the presence of antibodies directed toward Cx3cr1. Increased proportions of oligodendrocytic cells (defined by markers such as PDGFRa and, ultimately, myelin itself) could in principle be achieved through an expansion of the population of multipotent precursor cells, specification of these precursors toward the oligodendrocyte lineage, enhanced oligodendrocytic differentiation, or survival. Labeling experiments with BrdU showed that fractalkine did not
Neuron 94, May 3, 2017 ª 2017 Elsevier Inc. 415
Neuron
Previews
affect proliferation. Likewise, cell development beginning at E13/ survival, as marked by E14 when these cells first arrive condensed apoptotic nuclei, at the germinal layers of the prewas unperturbed. However, the sumptive cortex and extending authors did observe an increase to at least during the first few in the relative proportion of weeks of postnatal life. A key PDGFRa-positive oligodendroMGE-derived ligand is the checyte cells within the cultures, mokine fractalkine, which, via its suggesting that fractalkine funccognate receptor Cx3cr1, protions to increase the differentiamotes maturation of oligodention of committed oligodendrodrocyte progenitors. It must be cyte progenitors. Importantly, noted (and the authors concede) the authors demonstrated that that fractalkine does not have fractalkine can stimulate oligoan exclusive license to practice dendrocytic differentiation of oligodendrocyte population conboth embryonic and postnatal trol. In particular, MGE-derived oligodendrocyte precursors. interneurons appear to promote Turning again to animal mitosis of cortical progenitors in models, the authors found that culture and in animals (Figures 1 MGE-derived interneurons exand 2, respectively, in Voronova press fractalkine mRNA at E17 et al., 2017), whereas fractalwithin the germinal zones and kine’s effects are confined to difcortical plate. By P4, fractalkine ferentiation. Gas6 was identified mRNA expression is robust as another potential interthroughout the cortical mantle. neuron-secreted ligand by the Likewise, by E17, Sox2-positive authors’ in silico screen, and the progenitors in the ventricular interneuron transmitter GABA itand subventricular zones co-exself has been shown to impact press Olig2 and Cx3cr1 mRNA. oligodendrocyte biology (see Co-expression of Sox2, Olig2, Voronova et al. and references and Cx3cr1 is sustained through therein). PDGF is also expressed P4 in cells within and immediin neurons, and a broad body ately basal to the subventricuof data highlights a role for lar zone. PDGF in oligodendrogenesis, The authors were also able to for example (Calver et al., Figure 1. Anatomical Backdrop to Voronova et al. confirm a role for Cx3cr1 in 1998). Curiously, none of these (Bottom panel) A traffic jam in the developing neocortex: coronal neuron-derived factors seem to cortical oligodendrogenesis by section of E12.5 telencephalon, adapted from Kessaris et al. (2006) and Yokota et al. (2007). Beginning at E12.5, interneurons born in the meet the needs of the first wave showing that Cx3cr1 null mice MGE and (to a somewhat lesser extent) in the LGE begin radial of oligodendrocyte progenitors exhibit a reduction in the propormigration toward the neocortex. At the same time, the first of three born in the MGE that arrive in tion of cortical Olig2-positive waves of oligodendrocyte progenitors is born in the MGE and begins migration ventrally and also dorsally toward the neocortex. A second the presumptive cortex at around cells. A worry with the Cx3cr1 burst of oligodendrocyte progenitors derived from the LGE will begin E16. By P10, the majority of these null mouse model was that other migration a few days later. A third wave of progenitors will be born MGE-derived oligodendrocyte cell types (notably microglia) locally within the cortex beginning at around P0. (Middle panel) The state of affairs at E15 (from Voronova et al., 2017): MGE-derived inprogenitors have been cleared express the receptor. Accordterneurons have arrived in the neocortex, where they intermingle with from the cortex and corpus calingly, the observed effects on Pax6-positive radial precursor cells within the germinal layers and also losum to be replaced by progenOlig2-positive cell types might with nestin-positive processes from these cells in the upper cortical itors derived from the LGE and be non-cell autonomous. To layers. The first wave of MGE-derived oligodendrocyte progenitors will arrive a day or so later (Kessaris et al., 2006). (Top panel) The P0 cortex also locally born progenitors address this concern, the (from Voronova et al., 2017): MGE-derived interneurons in close (see Figure 1 and also Kessaris authors electroporated Cx3cr1 proximity to oligodendrocyte progenitors in the apical cortex. At this et al., 2006). shRNAs in the PB transposon stage, most of the MGE-derived oligodendrocyte progenitors have already been eliminated, so these progenitors are derived from the Are there any practical oversystem into the cortex of LGE or born locally (Kessaris et al., 2006). tones to the fractalkine:Cx3cr1 E14 mouse embryos. These signaling axis? Studies with mufocused knockdown experirine models of multiple sclerosis ments confirmed that suppression of Cx3cr1 selectively reduced the Collectively, the studies of Voronova (MS) have shown that Cx3cr1 null mice abundance of oligodendrocyte lineage et al. (2017) define a role for MGE-derived exhibit aberrant recruitment of Olig2/ cells and that microglia were not targeted interneurons in modulation of oligoden- PDGFRa-positive oligodendrocyte proby the electroporation protocol. drocyte formation at multiple stages of genitor cells into regions of demyelination 416 Neuron 94, May 3, 2017
Neuron
Previews induced by cuprizone or experimental autoimmune encephalomyelitis (Garcia et al., 2013; Lampron et al., 2015). Microglia express Cx3cr1, and these prior studies focused on defective microglia as the underlying cause of the remyelination phenotype. However, the observations of Voronova et al. (2017) suggest that the biologically relevant target of Cx3cr1 ablation in these MS models may be the oligodendrocyte precursors or progenitors. On another disease front, oligodendrocyte progenitors are an attractive ‘‘cellof-origin’’ candidate for malignant glioma, and neuron-derived factors are an emerging area of focus for these tumors. One recent study highlights a link between neuronal activity and glioma growth through secretion of neuroligin-3 (Venkatesh et al., 2015). However, the work of Voronova et al. (2017) suggests that neuron-derived fractalkine might work in opposition to glioma growth. The Olig2 transcription factor—essential to forma-
tion of oligodendrocyte progenitors—is likewise essential for maintaining ‘‘stemness’’ and tumorigenic potential of patient-derived glioma cell lines (Suva` et al., 2014). Olig2 also happens to associate with the Cx3cr1 gene in postnatal oligodendrocyte progenitors (Yu et al., 2013). The authors suggest that fractalkine might oppose glioma growth by promoting differentiation of Olig2-positive tumor initiating cells further down the oligodendrocyte lineage. Those of us who battle these tumors at the bench and at the bedside would look forward with great interest to a test of this hypothesis.
Kessaris, N., Fogarty, M., Iannarelli, P., Grist, M., Wegner, M., and Richardson, W.D. (2006). Nat. Neurosci. 9, 173–179. Lampron, A., Larochelle, A., Laflamme, N., Pre´fontaine, P., Plante, M.-M., Sa´nchez, M.G., Yong, V.W., Stys, P.K., Tremblay, M.-E`., and Rivest, S. (2015). J. Exp. Med. 212, 481–495. Salzer, J.L. (2015). Cold Spring Harb. Perspect. Biol. 7, a020529. Suva`, M.L., Rheinbay, E., Gillespie, S.M., Patel, A.P., Wakimoto, H., Rabkin, S.D., Riggi, N., Chi, A.S., Cahill, D.P., Nahed, B.V., et al. (2014). Cell 157, 580–594. Venkatesh, H.S., Johung, T.B., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E.M., Mount, C.W., Polepalli, J., Mitra, S.S., et al. (2015). Cell 161, 803–816. Voronova, A., Yuzwa, S.A., Wang, B., Zahr, S., Syal, C., Wang, J., Kaplan, D.R., and Miller, F.D. (2017). Neuron 94, this issue, 500–516.
REFERENCES Calver, A.R., Hall, A.C., Yu, W.P., Walsh, F.S., Heath, J.K., Betsholtz, C., and Richardson, W.D. (1998). Neuron 20, 869–882. Garcia, J.A., Pino, P.A., Mizutani, M., Cardona, S.M., Charo, I.F., Ransohoff, R.M., Forsthuber, T.G., and Cardona, A.E. (2013). J. Immunol. 191, 1063–1072.
Yokota, Y., Gashghaei, H.T., Han, C., Watson, H., Campbell, K.J., and Anton, E.S. (2007). PLoS ONE 2, e794. Yu, Y., Chen, Y., Kim, B., Wang, H., Zhao, C., He, X., Liu, L., Liu, W., Wu, L.M.N., Mao, M., et al. (2013). Cell 152, 248–261.
Lethal Giant Lineage Tracing: Mutating Locally, Acting Globally Aslam Abbasi Akhtar,1,2 Hannah Park,1,2 and Joshua J. Breunig1,2,3,4,* 1Board
of Governors Regenerative Medicine Institute of Biomedical Sciences 3Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 4Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2017.04.030 2Department
The generation of neurons and glia from radial glia progenitors is critical to proper neocortical development but the mechanisms regulating their deterministic production are unclear. In this issue of Neuron, Beattie et al. (2017) use elegant MADM-based lineage tracing to demonstrate cell-intrinsic and global functions for Lgl1 during neocortical development.
Radial glia progenitors (RGPs) are the principal neural precursor type in the developing neocortex, residing in the continuum of neural stem cell types between early neuroepithelial cells and postnatal neural stem cells (Breunig et al., 2011). As such, RGPs are responsible for gener-
ating the diversity of neural types in the forebrain, including neurons, glia, ependymal cells, and persistent neural progenitor populations. Previous work has shown a deterministic pattern of cellular output from individual RGPs in terms of neuron generation (8–9 per RGP) and
gliogenic potential (1 in 6 RGP eventually generating glia) (Gao et al., 2014). Though this seminal work provided insight into the intrinsic potential of individual RGPs, the mechanisms leading to the robust generation of appropriate daughter cell types remain incompletely understood.
Neuron 94, May 3, 2017 ª 2017 Elsevier Inc. 417