Ascl1/Mash1 Promotes Brain Oligodendrogenesis during Myelination and Remyelination
Open accessAbstract
Oligodendrocytes are the myelin-forming cells of the CNS. They differentiate from oligodendrocyte precursor cells (OPCs) that are produced from progenitors throughout life but more actively during the neonatal period and in response to demyelinating insults. An accurate regulation of oligodendrogenesis is required to generate oligodendrocytes during these developmental or repair processes. We hypothesized that this regulation implicates transcription factors, which are expressed by OPCs and/or their progenitors. Ascl1/Mash1 is a proneural transcription factor previously implicated in embryonic oligodendrogenesis and operating in genetic interaction with Olig2, an essential transcriptional regulator in oligodendrocyte development. Herein, we have investigated the contribution of Ascl1 to oligodendrocyte development and remyelination in the postnatal cortex. During the neonatal period, Ascl1 expression was detected in progenitors of the cortical subventricular zone and in cortical OPCs. Different genetic approaches to delete Ascl1 in cortical progenitors or OPCs reduced neonatal oligodendrogenesis, showing that Ascl1 positively regulated both OPC specification from subventricular zone progenitors as well as the balance between OPC differentiation and proliferation. Examination of remyelination processes, both in the mouse model for focal demyelination of the corpus callosum and in multiple sclerosis lesions in humans, indicated that Ascl1 activity was upregulated along with increased oligodendrogenesis observed in remyelinating lesions. Additional genetic evidence indicated that remyelinating oligodendrocytes derived from Ascl1(+) progenitors/OPCs and that Ascl1 was required for proper remyelination. Together, our results show that Ascl1 function modulates multiple steps of OPC development in the postnatal brain and in response to demyelinating insults.
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In OPCs, there was early upregulation of several transcription factors and Notch ligands known to regulate differentiation to oligodendrocytes after loss of surrounding oligodendrocytes.
“In OPCs, there was early upregulation of several transcription factors (OLIG1, OLIG2, SOX10, SOX8, PRRX1, ASCL1) and Notch ligands (DLL1, DLL3) known to regulate differentiation78–81 to oligodendrocytes after loss of surrounding oligodendrocytes (Fig. 7e, right, and Fig. 7g).”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [80]
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Direct conversion of fibroblasts to functional neurons by defined factors
Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Südhof, T. C., & Wernig, M. (2010) · Nature · doi:10.1038/nature08797 · Cited by 3,017 · see citing works
Kessaris, N., Fogarty, M., Iannarelli, P., Grist, M., Wegner, M., & Richardson, W. D. (2006) · Nature Neuroscience · doi:10.1038/nn1620 · Cited by 1,195 · see citing works
The bHLH Transcription Factors OLIG2 and OLIG1 Couple Neuronal and Glial Subtype Specification
Zhou, Q., & Anderson, D. J. (2002) · Cell · doi:10.1016/s0092-8674(02)00677-3 · Cited by 1,059 · cited 2× · see citing works
“2 (Qi et al., 2001; Sun et al., 2001; Zhou et al., 2001; Zhou and Anderson, 2002; Stolt et al., 2003, 2004; Arnett et al., 2004; Kitada and Rowitch, 2006; Liu et al., 2007; Cai et al., 2010).”
BackgroundAge-dependent fate and lineage restriction of single NG2 cells
Zhu, X., Hill, R. A., Dietrich, D., Komitova, M., Suzuki, R., & Nishiyama, A. (2011) · Development · doi:10.1242/dev.047951 · Cited by 464 · see citing works
bHLH Transcription Factor Olig1 Is Required to Repair Demyelinated Lesions in the CNS
Arnett, H. A., Fancy, S. P. J., Alberta, J. A., Zhao, C., Plant, S. R., Kaing, S., Raine, C. S., Rowitch, D. H., Franklin, R. J. M., & Stiles, C. D. (2004) · Science · doi:10.1126/science.1103709 · Cited by 416 · see citing works
Petryniak, M. A., Potter, G. B., Rowitch, D. H., & Rubenstein, J. L. R. (2007) · Neuron · doi:10.1016/j.neuron.2007.06.036 · Cited by 371 · see citing works
Chen, Y., Wu, H., Wang, S., Koito, H., Li, J., Ye, F., Hoang, J., Escobar, S. S., Gow, A., Arnett, H. A., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2410 · Cited by 346 · see citing works
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Research works printed but not linked: 53
- Aguirre A Dupree JL Mangin JM Gallo V A functional role for EGFR signaling in myelination and remyelination Nat Neurosci 2007 10 990 1002 CrossRef Medline 17618276
- Bertrand N Castro DS Guillemot F Proneural genes and the specification of neural cell types Nat Rev Neurosci 2002 3 517 530 CrossRef Medline 12094208
- Bhat RV Axt KJ Fosnaugh JS Smith KJ Johnson KA Hill DE Kinzler KW Baraban JM Expression of the APC tumor suppressor protein in oligodendroglia Glia 1996 17 169 174 CrossRef Medline 8776583
- Boda E Viganò F Rosa P Fumagalli M Labat-Gest V Tempia F Abbracchio MP Dimou L Buffo A The GPR17 receptor in NG2 expressing cells: focus on in vivo cell maturation and participation in acute trauma and chronic damage Glia 2011 59 1958 1973 CrossRef Medline 21956849
- Boutin C Diestel S Desoeuvre A Tiveron MC Cremer H Efficient in vivo electroporation of the postnatal rodent forebrain PLoS One 2008 3 e1883 CrossRef Medline 18382666 PMC2270900
- Cai J Zhu Q Zheng K Li H Qi Y Cao Q Qiu M Co-localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes Glia 2010 58 458 468 CrossRef Medline 19780200 PMC2807475
- Casarosa S Fode C Guillemot F Mash1 regulates neurogenesis in the ventral telencephalon Development 1999 126 525 534 Medline 9876181
- Castro DS Martynoga B Parras C Ramesh V Pacary E Johnston C Drechsel D Lebel-Potter M Garcia LG Hunt C Dolle D Bithell A Ettwiller L Buckley N Guillemot F A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets Genes Dev 2011 25 930 945 CrossRef Medline 21536733 PMC3084027
- Fancy SP Zhao C Franklin RJ Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS Mol Cell Neurosci 2004 27 247 254 CrossRef Medline 15519240
- Fancy SP Baranzini SE Zhao C Yuk DI Irvine KA Kaing S Sanai N Franklin RJ Rowitch DH Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS Genes Dev 2009 23 1571 1585 CrossRef Medline 19515974 PMC2704469
- Franklin RJ ffrench-Constant C Remyelination in the CNS: from biology to therapy Nat Rev Neurosci 2008 9 839 855 CrossRef Medline 18931697
- Gokhan S Marin-Husstege M Yung SY Fontanez D Casaccia-Bonnefil P Mehler MF Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression J Neurosci 2005 25 8311 8321 CrossRef Medline 16148239 PMC6725536
- Gorski JA Talley T Qiu M Puelles L Rubenstein JL Jones KR Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage J Neurosci 2002 22 6309 6314 Medline 12151506 PMC6758181
- Hack MA Sugimori M Lundberg C Nakafuku M Götz M Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6 Mol Cell Neurosci 2004 25 664 678 CrossRef Medline 15080895
- Hall A Giese NA Richardson WD Spinal cord oligodendrocytes develop from ventrally derived progenitor cells that express PDGF alpha-receptors Development 1996 122 4085 4094 Medline 9012528
- Ivanova A Nakahira E Kagawa T Oba A Wada T Takebayashi H Spassky N Levine J Zalc B Ikenaka K Evidence for a second wave of oligodendrogenesis in the postnatal cerebral cortex of the mouse J Neurosci Res 2003 73 581 592 CrossRef Medline 12929126
- Kitada M Rowitch DH Transcription factor co-expression patterns indicate heterogeneity of oligodendroglial subpopulations in adult spinal cord Glia 2006 54 35 46 CrossRef Medline 16673374
- Kondo T Raff M Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation Development 2000 127 2989 2998 Medline 10862737
- Lassmann H Neuropathology in multiple sclerosis: new concepts Mult Scler 1998 4 93 98 CrossRef Medline 9762654
- Li H de Faria JP Andrew P Nitarska J Richardson WD Phosphorylation regulates OLIG2 cofactor choice and the motor neuron-oligodendrocyte fate switch Neuron 2011 69 918 929 CrossRef Medline 21382552 PMC3093612
- Ligon KL Fancy SP Franklin RJ Rowitch DH Olig gene function in CNS development and disease Glia 2006 54 1 10 CrossRef Medline 16652341
- Liu Z Hu X Cai J Liu B Peng X Wegner M Qiu M Induction of oligodendrocyte differentiation by Olig2 and Sox10: evidence for reciprocal interactions and dosage-dependent mechanisms Dev Biol 2007 302 683 693 CrossRef Medline 17098222
- Lu QR Cai L Rowitch D Cepko CL Stiles CD Ectopic expression of Olig1 promotes oligodendrocyte formation and reduces neuronal survival in developing mouse cortex Nat Neurosci 2001 4 973 974 CrossRef Medline 11574831
- Menn B Garcia-Verdugo JM Yaschine C Gonzalez-Perez O Rowitch D Alvarez-Buylla A Origin of oligodendrocytes in the subventricular zone of the adult brain J Neurosci 2006 26 7907 7918 CrossRef Medline 16870736 PMC6674207
- Miguez A Ducret S Di Meglio T Parras C Hmidan H Haton C Sekizar S Mannioui A Vidal M Kerever A Nyabi O Haigh J Zalc B Rijli FM Thomas JL Opposing roles for Hoxa2 and Hoxb2 in hindbrain oligodendrocyte patterning J Neurosci 2012 32 17172 17185 CrossRef Medline 23197710 PMC6621859
- Mizuguchi R Sugimori M Takebayashi H Kosako H Nagao M Yoshida S Nabeshima Y Shimamura K Nakafuku M Combinatorial roles of Olig2 and neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons Neuron 2001 31 757 771 CrossRef Medline 11567615
- Nait-Oumesmar B Decker L Lachapelle F Avellana-Adalid V Bachelin C Baron-Van Evercooren A Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination Eur J Neurosci 1999 11 4357 4366 CrossRef Medline 10594662
- Nait-Oumesmar B Picard-Riera N Kerninon C Decker L Seilhean D Höglinger GU Hirsch EC Reynolds R Baron-Van Evercooren A Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors Proc Natl Acad Sci U S A 2007 104 4694 4699 CrossRef Medline 17360586 PMC3025281
- Nait-Oumesmar B Picard-Riéra N Kerninon C Baron-Van Evercooren A The role of SVZ-derived neural precursors in demyelinating diseases: from animal models to multiple sclerosis J Neurol Sci 2008 265 26 31 CrossRef Medline 17961598
- Pacary E Heng J Azzarelli R Riou P Castro D Lebel-Potter M Parras C Bell DM Ridley AJ Parsons M Guillemot F Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling Neuron 2011 69 1069 1084 CrossRef Medline 21435554 PMC3383999
- Parras CM Galli R Britz O Soares S Galichet C Battiste J Johnson JE Nakafuku M Vescovi A Guillemot F Mash1 specifies neurons and oligodendrocytes in the postnatal brain EMBO J 2004 23 4495 4505 CrossRef Medline 15496983 PMC526464
- Parras CM Hunt C Sugimori M Nakafuku M Rowitch D Guillemot F The proneural gene Mash1 specifies an early population of telencephalic oligodendrocytes J Neurosci 2007 27 4233 4242 CrossRef Medline 17442807 PMC6672315
- Qi Y Cai J Wu Y Wu R Lee J Fu H Rao M Sussel L Rubenstein J Qiu M Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor Development 2001 128 2723 2733 Medline 11526078
- Rivers LE Young KM Rizzi M Jamen F Psachoulia K Wade A Kessaris N Richardson WD PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice Nat Neurosci 2008 11 1392 1401 CrossRef Medline 18849983 PMC3842596
- Scott CE Wynn SL Sesay A Cruz C Cheung M Gomez Gaviro MV Booth S Gao B Cheah KS Lovell-Badge R Briscoe J SOX9 induces and maintains neural stem cells Nat Neurosci 2010 13 1181 1189 CrossRef Medline 20871603
- Soriano P Generalized lacZ expression with the ROSA26 Cre reporter strain Nat Genet 1999 21 70 71 CrossRef Medline 9916792
- Spassky N Goujet-Zalc C Parmantier E Olivier C Martinez S Ivanova A Ikenaka K Macklin W Cerruti I Zalc B Thomas JL Multiple restricted origin of oligodendrocytes J Neurosci 1998 18 8331 8343 Medline 9763477 PMC6792828
- Srinivas S Watanabe T Lin CS William CM Tanabe Y Jessell TM Costantini F Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus BMC Dev Biol 2001 1 4 CrossRef Medline 11299042 PMC31338
- Staugaitis SM Trapp BD NG2-positive glia in the human central nervous system Neuron Glia Biol 2009 5 35 44 CrossRef Medline 19785924
- Stolt CC Lommes P Sock E Chaboissier MC Schedl A Wegner M The Sox9 transcription factor determines glial fate choice in the developing spinal cord Genes Dev 2003 17 1677 1689 CrossRef Medline 12842915 PMC196138
- Stolt CC Lommes P Friedrich RP Wegner M Transcription factors Sox8 and Sox10 perform non-equivalent roles during oligodendrocyte development despite functional redundancy Development 2004 131 2349 2358 CrossRef Medline 15102707
- Sugiarto S Persson AI Munoz EG Waldhuber M Lamagna C Andor N Hanecker P Ayers-Ringler J Phillips J Siu J Lim DA Vandenberg S Stallcup W Berger MS Bergers G Weiss WA Petritsch C Asymmetry-defective oligodendrocyte progenitors are glioma precursors Cancer Cell 2011 20 328 340 CrossRef Medline 21907924 PMC3297490
- Sugimori M Nagao M Bertrand N Parras CM Guillemot F Nakafuku M Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord Development 2007 134 1617 1629 CrossRef Medline 17344230
- Sun T Echelard Y Lu R Yuk DI Kaing S Stiles CD Rowitch DH Olig bHLH proteins interact with homeodomain proteins to regulate cell fate acquisition in progenitors of the ventral neural tube Curr Biol 2001 11 1413 1420 CrossRef Medline 11566099
- Tekki-Kessaris N Woodruff R Hall AC Gaffield W Kimura S Stiles CD Rowitch DH Richardson WD Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon Development 2001 128 2545 2554 Medline 11493571
- Vierbuchen T Wernig M Molecular roadblocks for cellular reprogramming Mol Cell 2012 47 827 838 CrossRef Medline 23020854 PMC3809030
- Waclaw RR Wang B Pei Z Ehrman LA Campbell K Distinct temporal requirements for the homeobox gene Gsx2 in specifying striatal and olfactory bulb neuronal fates Neuron 2009 63 451 465 CrossRef Medline 19709628 PMC2772064
- Wang S Sdrulla A Johnson JE Yokota Y Barres BA A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development Neuron 2001 29 603 614 CrossRef Medline 11301021
- Watanabe M Hadzic T Nishiyama A Transient upregulation of Nkx2.2 expression in oligodendrocyte lineage cells during remyelination Glia 2004 46 311 322 CrossRef Medline 15048854
- Yue T Xian K Hurlock E Xin M Kernie SG Parada LF Lu QR A critical role for dorsal progenitors in cortical myelination J Neurosci 2006 26 1275 1280 CrossRef Medline 16436615 PMC6674567
- Yun K Mantani A Garel S Rubenstein J Israel MA Id4 regulates neural progenitor proliferation and differentiation in vivo Development 2004 131 5441 5448 CrossRef Medline 15469968
- Zhou Q Choi G Anderson DJ The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2 Neuron 2001 31 791 807 CrossRef Medline 11567617
- Zhu X Zuo H Maher BJ Serwanski DR LoTurco JJ Lu QR Nishiyama A Olig2-dependent developmental fate switch of NG2 cells Development 2012 139 2299 2307 CrossRef Medline 22627280 PMC3367441
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- Authors
- Nakatani, H., Martin, E., Hassani, H., Clavairoly, A., Maire, C. L., Viadieu, A., Kerninon, C., Delmasure, A., Frah, M., Weber, M., Nakafuku, M., Zalc, B., Thomas, J.-L., Guillemot, F., Nait-Oumesmar, B., & Parras, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- National Institute for Medical Research (GB)
- Cincinnati Children's Hospital Medical Center (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-06-05
- Volume
- 33
- Issue
- 23
- Pages
- 9752-9768
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3892435
- OpenAlex
- W1995960135
- Cited by
- 158
- References
- 7
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 11 · 2023: 13 · 2022: 10 · 2021: 15 · 2020: 16 · 2019: 9 · 2018: 10 · 2017: 16 · 2016: 10 · 2015: 15 · 2014: 12 · 2013: 4
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- HAL (submittedVersion)
- Funders
- Parkinson's UK (G0909)
- National Institute of Neurological Disorders and Stroke (R01NS069893)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- ASCL1, oligodendrogenesis, remyelination, oligodendrocyte precursor cells, myelination, proneural transcription factors, Olig2, demyelination, multiple sclerosis, corpus callosum, postnatal brain development
- MeSH terms
- Animals, Brain, Female, Humans, Male, Mice, Transgenic, Myelin Sheath, Nerve Fibers, Myelinated, Oligodendroglia, Mice, Knockout, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Neural Stem Cells
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