Neural bHLH Genes Control the Neuronal versus Glial Fate Decision in Cortical Progenitors

Nieto, Marta; Schuurmans, Carol; Britz, Olivier; Guillemot, François

doi:10.1016/s0896-6273(01)00214-8

Cited by 470 publications

(332 citation statements)

References 74 publications

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“…7b). In addition, in Ngn2 knockout mouse cortices, where Ngn1 expression is also reduced because of Ngn2 deficiency 38 , we observed precocious activation of the astrogliogenic machinery and early onset of astroglial gene expression (Fig. 7c, Supplementary Fig.…”

Section: Reduced Expression Of Proneural Genes Derepresses Jak-statmentioning

confidence: 78%

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A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

et al. 2005

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During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokineinduced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.During embryonic development, the generation of three major neural cell types (neurons, astrocytes, and oligodendrocytes) in the CNS occurs sequentially, whereby almost all neurons are generated before the appearance of glial cells 1,2 , with the exception of a few COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2014 November 06. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sites of postnatal and adult neurogenesis such as the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the forebrain 3 . This strategy of building the CNS through sequential production of neurons and glia has become more comprehensible, as recent findings have demonstrated that glial cells are important in critical neuronal maturation processes such as axonal path finding and synapse formation [4][5][6] . It is conceivable that delayed or precocious production of glial cells may lead to inappropriate wiring, disorganization, and eventually, dysfunction of the CNS.The 'neurons-first, glia-second' differentiation theme for neural progenitors can be recapitulated in culture. Cortical neural progenitor stem cells isolated from relatively early embryonic stages (for example, mouse embryonic day (E) 10-11) give rise to neurons, not glial cells, after short-term culturing (fewer than 4 d), whereas cortical progenitors isolated from perinatal stages tend to differentiate into astrocytes under the same culture conditions 7 .In addition, both E10-11 cortical progenitors and embryonic stem cell-derived neural stem or progenitor cells (NSCs or NPCs) switch from being neurogenic to gliogenic over time in vitro 8,9 , suggesting that the molecular switch for the transition from neurogenesis to gliogenesis may be internally programmed in neural progenitors.S...

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Section: Reduced Expression Of Proneural Genes Derepresses Jak-statmentioning

confidence: 78%

“…After dissection, cells were treated with or without LIF (100 ng ml −1 ) for 20 min to induce STAT phosphorylation and activation. Neurogenin-2 knockout mice were generated by F.G.'s group 38 . Mice were handled in accordance with the Animal Research Committee of the University of California, Los Angeles.…”

Section: Micementioning

confidence: 99%

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

et al. 2005

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“…5 Similarly, Wnts have been recently found to enhance neurogenesis from hippocampus-derived precursors, through the stimulation of neuroblast proliferation. 6 Also, pro-neural transcription factors of the helix-loop-helix family, such as neurogenin and Mash1 32,33 have been reported to enhance neuron generation through an increased proliferation of their progenitors. In fact, Mash1 deletion mutant mice show decreased cell proliferation, and reduced brain size and neuronal generation/ differentiation in the ventral forebrain.…”

Section: Discussionmentioning

confidence: 99%

Bcl-XL modulates the differentiation of immortalized human neural stem cells

et al. 2007

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Understanding basic processes of human neural stem cell (hNSC) biology and differentiation is crucial for the development of cell replacement therapies. Bcl-X L has been reported to enhance dopaminergic neuron generation from hNSCs and mouse embryonic stem cells. In this work, we wanted to study, at the cellular level, the effects that Bcl-X L may exert on cell death during differentiation of hNSCs, and also on cell fate decisions and differentiation. To this end, we have used both v-myc immortalized (hNS1 cell line) and non-immortalized neurosphere cultures of hNSCs. In culture, using different experimental settings, we have consistently found that Bcl-X L enhances neuron generation while precluding glia generation. These effects do not arise from a glia-to-neuron shift (changes in fate decisions taken by precursors) or by only cell death counteraction, but, rather, data point to Bcl-X L increasing proliferation of neuronal progenitors, and inhibiting the differentiation of glial precursors. In vivo, after transplantation into the aged rat striatum, Bcl-X L overexpressing hNS1 cells generated more neurons and less glia than the control ones, confirming the results obtained in vitro. These results indicate an action of Bcl-X L modulating hNSCs differentiation, and may be thus important for the future development of cell therapy strategies for the diseased mammalian brain. The efficient generation of human neurons and glia from stem cells is the object of intense investigation, in the context of basic and preclinical cell replacement research. 1,2 Different means of genetic and epigenetic manipulations of stem cell cultures are being tested, aiming at enhancing their ability to generate the desired cell types. [3][4][5][6] In previous studies, we and others have demonstrated that Bcl-X L overexpression has a major impact on the generation of dopaminergic neurons from human neural stem cells (hNSCs) and mouse embryonic stem cells (mES). 7,8 Also, recent data from conditional Bcl-X L mutant mice add support to these observations. 9,10 In the present study, we are extending these observations and analyzing in detail the effects of Bcl-X L on hNSCs differentiation, focusing on precursor cell fate choices, cell death, and precursor proliferation.Bcl-X L is the most potent antiapoptotic protein among Bcl-2 family members, both in vitro and in vivo. 11-14 More specifically, Bcl-X L is essential for neuronal survival during brain development and in the adult central nervous system (CNS) (knockout mice and gene-expression studies 15,16 ). In addition to its antiapoptotic role, recent studies have described new roles of Bcl-X L in cell physiology -effects on Ca 2 þ homeostasis and gene expression 17 and synaptic transmission regulation 18 -under not necessarily apoptotic conditions. Several other studies have also described the role of Bcl-X L in the control of cell cycle, 19,20 a process well known to be tightly linked to progression of precursor cells toward neuronal and glia differentiation. 21,22 In this work, we aimed...

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“…Notably, most of these cells expressed the radial glial marker BLBP, which is characteristic of precursors committed toward an astrocytic lineage ( Supplementary Fig. 3) 23,24 .…”

Section: Sip1 Controls the Timing Of Glial Precursor Specificationmentioning

confidence: 99%

Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

et al. 2009

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The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.

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Neural bHLH Genes Control the Neuronal versus Glial Fate Decision in Cortical Progenitors

Cited by 470 publications

References 74 publications

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

Bcl-XL modulates the differentiation of immortalized human neural stem cells

Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

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