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The bHLH Transcription Factors OLIG2 and OLIG1 Couple Neuronal and Glial Subtype Specification
Open accessAbstract
OLIG1 and OLIG2 are basic-helix-loop-helix (bHLH) transcription factors expressed in the pMN domain of the spinal cord, which sequentially generates motoneurons and oligodendrocytes. In Olig1/2 double-mutant mice, motoneurons are largely eliminated, and oligodendrocyte differentiation is abolished. Lineage tracing data suggest that Olig1(-/-)2(-/-) pMN progenitors instead generate V2 interneurons and then astrocytes. This apparent conversion likely reflects independent roles for OLIG1/2 in specifying motoneuron and oligodendrocyte fates. Olig genes therefore couple neuronal and glial subtype specification, unlike proneural bHLH factors that control the neuron versus glia decision. Our results suggest that in the spinal cord, Olig and proneural genes comprise a combinatorial code for the specification of neurons, astrocytes, and oligodendrocytes, the three fundamental cell types of the central nervous system.
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“Cell type-specific transcription factor expression is important for cell fate determination and cell differentiation (e.g., Neu-roD for specification of neuron cell fate, Olig2 for specification of oligodendrocyte fate, and GM98/Myrf for oligodendrocyte differentiation; Lee et al., 1995;Zhou and Anderson, 2002;Emery et al., 2009).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Zhou and Anderson, 2002
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“In heterozygotes, Olig2-hGFP -derived precursors gave is restricted to oligodendrocyte precursors (Lu et al., 2000; Zhou et al., 2000), nearly all OLIG2-positive cells rise to Islet1/2 (cid:2) motoneurons (Figure 3A, yellow cells) but not Chx10 (cid:2) V2 interneurons (Figure 3B).”
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“In heterozygotes, Olig2-hGFP -derived precursors gave is restricted to oligodendrocyte precursors (Lu et al., 2000; Zhou et al., 2000), nearly all OLIG2-positive cells rise to Islet1/2 (cid:2) motoneurons (Figure 3A, yellow cells) but not Chx10 (cid:2) V2 interneurons (Figure 3B).”
InfluentialSelf-citation
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“At all stages of development, priOPCs, OPCs and OLs express Olig2, an essential regulator of OL lineage speci fi cation 3,57,58 .”
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“…D) were enriched for the OLIG1 and OLIG2 co-expression networks (p = 0.01 and 0.04, respectively), which are implicated in stem-like identity in glioma (Aguirre-Cruz et al., 2004; Ligon et al., 2004, 2007) and early phases of glial cell development (Novitch et al., 2001; Zhou and Anderson, 2002).”
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“Expression of OLIG2 is restricted to the central nervous system and determines oligodendrocyte and astrocyte fate determination in the developing brain [28, 50, 51].”
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Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2.
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“In particular, pMN precursor cells first generate motor neurons during neurogenesis, and later produce OPCs after motor neuron formation is complete (Lu et al., 2002; Park et al., 2002b; Zhou and Anderson, 2002).”
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“In particular, OLIG2 and Neurog2 promote transcription of downstream motor neuronal genes, such as homeobox gene Hb9, early in development 144–146 .”
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“169 Meanwhile, Hu et al. (2012) reported that the overexpression of Olig2 genes could increase NSCs differentiation into ODCs in SCI animal models and thus cause behavioral improvement following traumatic SCI. 25 The F3.”
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“Oligodendrocytes and motor neurons were thought to derive from a common precursor expressing Olig 1 and Olig 2 (Zhou and Anderson 2002; Lu et al. 2000), but subsequent fate mapping studies identified multiple sources generating oligodendrocytes in the brain and spinal cord (Kessaris et al. 2006;…”
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“Consequently, we hypothesize that ID2-mediated inhibition of OLIG1/2 activity could modulate the histological phenotype of Ewing sarcoma/PNET tumors (75).”
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“We observed that transcription factors important for neuronal development, such as OLIG2 (Zhou and Anderson, 2002; Zhou et al., 2001), were upregulated in NGLY1 deficient neural progenitor cells (Figure 3d).”
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“bHLH transcription factors are essential for the normal growth and development of plants, and act against various abiotic stresses in plants [43].”
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“…transcription factor 1 (Olig1) is one of the intrinsic factors (Arnett et al., 2004; Emery et al., 2009; Q. R. Lu et al., 2002; Zhou & Anderson, 2002): in early stage OPCs, Olig1 localizes to the nucleus and promotes differentiation by inducing the expression of several myelin genes…”
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“Olig and proneural genes comprise a combinatorial code for the specification of neurons, astrocytes and oligodendrocytes, the three fundamental cell types of the central nervous system [ 38 ].”
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“The most important role of astrocytes is to nurture neighboring the same domain generates oligodendrocytes (Richardson et al. 2000; Zhou and Anderson 2002).”
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“The first identified transcription factors that modulate the development of OLs are Olig1 and Olig2 [96,97].”
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“A number of transcription factors (TFs), including Olig1/2 (Takebayashi et al. 2000; Lu et al. 2000, 2002; Zhou and Anderson 2002), Sox10 (reviewed in Wegner and Stolt 2005), Nkx2.”
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“2 are expressed in all cells of the lineage, while OPCs and pre-oligodendrocytes are specifically characterized by the expression of platelet-derived growth factor receptor α (PDGFR-α) and neuron-glial antigen 2 (NG2) [28, 29].”
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“Olig genes are among several TFs that couple neuronal and oligodendrocyte specification [60, 126].”
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“Zhou, Q., & Anderson, D. J. (2002).”
Backgroundc‐Abl‐induced Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells
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“Several studies have shown that Olig2, an oligodendroglial lineage determination factor, is involved in OPC specification, differentiation, and myelination (Lu et al., 2002; Wu et al., 2019; Zhou & Anderson, 2002).”
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“…bodies and the fine processes of microglia in the green channel with AF-488, and anti-S100β to label astrocyte cytoplasm and processes in the red channel with AF-594 (Figure 3), finding them to all to be morphologically discriminable (Dyck et al., 1993; Ito et al., 1998; Zhou and Anderson, 2002).”
BackgroundOlig1 expression pattern in neural cells during rat spinal cord development
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“12 Knocking out Olig1 and Olig2 individually or together affected differentiation and maturation of OLs, suggesting functional overlap in the CNS. 10,13,14 Until now, the role of Olig2 during development of spinal cord attracted more attention.”
Complex Networks Evolutionary Dynamics Using Genetic Algorithms
Aguilar-Hidalgo, D., Zurita, A., & Fernández, M. (2012) · International Journal of Bifurcation and Chaos in Applied Sciences and Engineering · doi:10.1142/s0218127412501568 · Cited by 7
Noble, M., & Mayer‐Pröschel, M. (2006) · Humana Press eBooks · doi:10.1385/1-59259-914-1:143 · Cited by 10
Libby, A., Rito, T., Radley, A., & Briscoe, J. (2024) · bioRxiv · doi:10.1101/2024.05.16.594506 · Cited by 6
“To assess whether the capture sequence affected system performance, we designed four gRNAs targeting the transcription factor OLIG2 , the knockout of which in the neural tube has been well documented ( 51, 52 ).”
MethodEvidence for compensatory evolution within pleiotropic regulatory elementsPreprint
Kliesmete, Z., Orchard, P., Lee, V. Y. K., Geuder, J., Krauß, S. M., Ohnuki, M., Jocher, J., Vieth, B., Enard, W., & Hellmann, I. (2024) · Genome Research · doi:10.1101/gr.279001.124 · Cited by 11
“(2021)that encompassesCREactivity measures for 10 mammalian species in four tissues.”
Sbp2l contributes to oligodendrocyte maturation through translational control in Tcf7l2 signaling
Yugami, M., Hayakawa‐Yano, Y., Ogasawara, T., Yokoyama, K., Furukawa, T., Hara, H., Hashikami, K., Tsuji, I., Takebayashi, H., Araki, S., et al. (2023) · iScience · doi:10.1016/j.isci.2023.108451 · Cited by 6
Long Noncoding RNAs in CNS Myelination and Disease
Zhang, J., Guan, M., Zhou, X., Berry, K., He, X., & Lu, Q. R. (2022) · The Neuroscientist · doi:10.1177/10738584221083919 · Cited by 6
Tsui, Y.-P., Lam, G., Wu, K. L., Li, M. T., Tam, K.-W., Shum, D. K., & Chan, Y. (2021) · Cells · doi:10.3390/cells10082166 · Cited by 7
“OPs were monitored for positivity of 4 key OP markers including Olig2, NG2, PDGFRα, and Sox10.”
MethodInfluentialJung‐Klawitter, S., & Opladen, T. (2018) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-018-0225-9 · Cited by 8
Kiecker, C. M., Graham, A., & Logan, M. P. O. (2016) · Journal of Developmental Biology · doi:10.3390/jdb4040036 · Cited by 7
Nakajima, M., Shimizu, R., Furuta, K., Sugino, M., Watanabe, T., Aoki, R., Okuyama, S., & Furukawa, Y. (2016) · Brain Research · doi:10.1016/j.brainres.2016.02.041 · Cited by 12
USP9X deletion elevates the density of oligodendrocytes within the postnatal dentate gyrus
Oishi, S., Zalucki, O. H., Premarathne, S., Wood, S., & Piper, M. (2016) · Neurogenesis · doi:10.1080/23262133.2016.1235524 · Cited by 6
“To investigate whether the elevated expression of oligodendrocyte-associated genes was reflected at a cellular level, we next performed immunocytochemical analyses of P14 Usp9x¡/Y; Emx1-Cre and Usp9x mice using antibodies against oligodendrocyte transcription factor 2 (Olig2), which identifies all cells within the oli…”
MethodZhou, L., Li, C.-J., Wang, Y., Xia, W., Yao, B., Jin, J., & Gui, J.-F. (2007) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2007.03.011 · Cited by 6
Maintaining Youth in Drosophila Neural Progenitors
Isshiki, T., & Doe, C. (2004) · Cell Cycle · doi:10.4161/cc.3.3.718 · Cited by 6
Olig genes and the genetic logic of CNS neural cell fate determination
Anderson, D. J., Choi, G. B., & Zhou, Q. (2002) · doi:10.1016/s1566-2772(02)00014-2 · Cited by 6
Self-citationMigration of Myelin-Forming Cells in the CNS
de Castro, F., & Zalc, B. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-397266-8.00035-1 · Cited by 8
Exploring a behavioral role for presynaptic inhibition at spinal sensory-motor synapses
Fink, A. J. (2013) · doi:10.7916/d8b85gh9 · Cited by 6
“GENETIC TARGETING OF PRESYNAPTIC INHIBITORY INTERNEURONS 76 (Novitch et al., 2001; Vallstedt et al., 2001; Zhou and Anderson, 2002), which conspire to specify motor neuronal fate.”
BackgroundThe Role of Oligodendrocytes in Alzheimer’s Disease Pathogenesis and Therapy
Guo, S., Yu, X., & Zhang, H. (2025) · Neuroglia · doi:10.3390/neuroglia6040046 · Cited by 5
Ward, E., Benowitz, L. I., Brunner, T. M., Bu, G., Cayouette, M., Canto-Soler, V., Mesquita, S. D., Polo, A. D., DiAntonio, A., Duan, X., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00858-5 · Cited by 7
“In the brain and spinal cord, combinatorial codes of regulatory gene networks are associated with greater progenitor cell diversity and increased complexity in temporal and spatial gene expression patterning [48–50].”
Medulloblastoma: biology and immunotherapy
Poggi, A. D., Reggiani, F., Azevedo, H. S., Raffaghello, L., & Pereira, R. C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1602930 · Cited by 5
Mu, Y.-W., Wei, Z., Sun, M., Li, J., Jiang, Y., Jiang, H., Ma, A., Zhu, C., & Chen, X. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf455 · Cited by 5
“Given Olig1’s reported expression in progenitors of motor neurons [ 64 ], we also performed ChAT immunofluorescence in the spinal cord to assess the development dynamics of motor neurons in OcKO mice.”
Karakaya, D., Lampe, K., Encinas, J. L., Duru, S., Peiro, L., Oge, H., Sánchez-Margallo, F., Oria, M., & Peiro, J. L. (2025) · Fluids and Barriers of the CNS · doi:10.1186/s12987-025-00630-3 · Cited by 5
“Additionally, Olig2 is a critical patterning factor in neurogenesis as well as oligodendrogenesis, and its downregulation results in an increased astrocytic lineage [62, 77].”
Dysregulation of Myelination in Focal Cortical Dysplasia Type II of the Human Frontal Lobe
Donkels, C., Häussler, U., Huber, S., Tiesmeyer, N., Demerath, T., Scheiwe, C. F., Shah, M., Heers, M., Urbach, H., Schulze-Bonhage, A., et al. (2024) · Glia · doi:10.1002/glia.24662 · Cited by 5
“…sip1 mRNAs were unaltered in both FCD types in line with a constant need of these transcription factors for the maturation and preservation of OLs (Zhou and Anderson 2002; Lu et al. 2002) and by unaltered binding capacities of OLIG2 to genes encoding structural myelin proteins as shown in our…”
Ghosh, S., Bhatti, G. K., Sharma, P. K., Kandimalla, R. J. L., Mastana, S. S., & Bhatti, J. S. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01434-5 · Cited by 7
“…it was demonstrated that double knock-out of both transcription factors Olig1 and Oligo2 in mice, recognized as bHLH transcription factors, fail to express OL, indicating that these Shh-expressed two transcription factors are essential for OL development (Zhou and Anderson 2002; Szu et al. 2021).”
Preventing recurrence in Sonic Hedgehog Subgroup Medulloblastoma using the OLIG2 inhibitor CT-179
Li, Y.-C., Lim, C., Dismuke, T., Malawsky, D., Oasa, S., Bruce, Z. C., Offenhäuser, C., Baumgartner, U., D'Souza, R., Edwards, S., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-2949436/v1 · Cited by 5
Altbürger, C., Rath, M., Armbruster, D., & Driever, W. (2023) · bioRxiv · doi:10.1101/2023.05.16.540944 · Cited by 5
“OLIG2 function is well characterized for spinal cord motorneurons, and it is crucial for oligodendrocyte formation, both developing from the ventral spinal cord primary motor neuron (pMN) domain (Lu et al., 2002; Meijer et al., 2012; Zhou and Anderson, 2002).”
BackgroundGotoh, H., Chimhanda, T. A., Nomura, T., & Ono, K. (2022) · FEBS Letters · doi:10.1002/1873-3468.14489 · Cited by 5
Malignant oligoastrocytoma in the spinal cord of a cat
Hasegawa, D., Aoshima, K., Sasaoka, K., Kobayashi, A., Takiguchi, M., & Kimura, T. (2022) · Journal of Veterinary Medical Science · doi:10.1292/jvms.22-0144 · Cited by 5
Merour, E., Hmidan, H., Marie, C., Helou, P.-H., Lu, H., Potel, A., Huré, J.-B., Clavairoly, A., Shih, Y.-P., Goudarzi, S., et al. (2022) · bioRxiv · doi:10.1101/2022.02.25.481980 · Cited by 5
“To improve our understanding of the mechanisms of OL differentiation, we searched for novel common targets of these key regulators, by generating and analyzing the common binding profiles of Olig2, Chd7, and Chd8, in gene regulatory elements of differentiating oligodendroglia.”
BackgroundMethodInfluentialXie, L.-S., Wang, W., Zhou, H.-Q., Han, Z.-J., Xu, J.-H., Xu, Z.-H., & Xiang, J.-J. (2022) · International Journal of Surgical Pathology · doi:10.1177/10668969221080076 · Cited by 5
“It is a transcription factor that is required for appropriate development of motor neurons and oligodendrocytes.(12) Immunohistochemical staining of OLIG2 is widely used in diagnosis of glial neoplasms and “neuronal neoplasms”, including oligodendroglioma, astrocytoma, and ependymoma, medulloblastoma, central neurocyt…”
BackgroundShringarpure, S., Wang, W. T., Jiang, Y., Acevedo, A., Dhamija, D., Cameron, B., Jubb, A. A., Yue, P., Sarov‐Blat, L., Gentleman, R. C., et al. (2021) · medRxiv · doi:10.1101/2021.06.09.21258643 · Cited by 4
Rapid induction of gliogenesis in OLIG2 and NKX2.2-expressing progenitors-derived spheroids
Yun, W., Kim, I. Y., Song, G., & You, S. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0455 · Cited by 5
Jiang, Q., Zagozewski, J., Godbout, R., & Eisenstat, D. (2020) · bioRxiv · doi:10.1101/2020.04.09.012385 · Cited by 5
“Deletion of both Olig1 and Olig2 resulted in significant loss of motor neurons in the spinal cord and total elimination of oligodendrocyte formation throughout the CNS (Q. Zhou & Anderson, 2002).”
BackgroundOlig3 Is Not Involved in the Ventral Patterning of Spinal Cord
Liu, Z., Hu, X.-M., Huang, C., Zheng, K., Takebayashi, H., Cao, C., & Qiu, M.-S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111076 · Cited by 5
Taking advantage of neural development to treat glioblastoma
Zhang, Z., & Lin, C.-C. J. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12655 · Cited by 4
“During neural development, Olig2 is expressed in the neural progenitor cells (NPCs) that give rise to neurons and to oligodendrocytes (Lu et al., 2000; Zhou & Anderson, 2002).”
BackgroundNkx2.2+ Progenitors Generate Somatic Motoneurons in the Chick Spinal Cord
Gotoh, H., Ono, K., Nomura, T., Takebayashi, H., Harada, H., Nakamura, H., & Ikenaka, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051581 · Cited by 5
Wada, Y., Yamauchi, K., Murakami, F., & Tanabe, Y. (2012) · Developmental Neurobiology · doi:10.1002/dneu.20861 · Cited by 5
Loh, W. T., Dheen, S., Jiang, B., Srinivasan, D. K., & Tay, S. (2011) · Histology and Histopathology · doi:10.14670/hh-26.965 · Cited by 5
“…of diabetic mice Olig2 is a basic helix-loop-helix transcription factor that is specifically expressed in progenitors of oligodendrocytes and motoneurons and its expression is induced by Shh in the neural tube (Lu et al., 2000; Zhou et al., 2000; Mizuguchi et al., 2001; Novitch et al., 2001).”
BackgroundTian, Y., Wang, Z.-W., Sun, M., Li, J., Zheng, W., Yang, F., & Zhang, Z.-Z. (2025) · Genes · doi:10.3390/genes16050573 · Cited by 4
“Among the key transcription factors, Olig1 and Olig2 are critical for oligodendrocyte lineage development [3–11].”
Metadata
- Authors
- Zhou, Q., & Anderson, D. J.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Anderson, David J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 109
- Issue
- 1
- Pages
- 61-73
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2125920059
- Cited by
- 1,059
- References
- 70
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 29 · 2023: 27 · 2022: 45 · 2021: 46 · 2020: 26 · 2019: 36 · 2018: 36 · 2017: 36 · 2016: 33 · 2015: 41 · 2014: 52 · 2013: 48 · 2012: 52
- FWCI
- 14.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01-NS23476, R01NS023476)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Olig2, Olig1, bHLH transcription factors, motor neurons, oligodendrocytes, astrocytes, proneural genes, lineage tracing
- MeSH terms
- Oligodendrocyte Transcription Factor 2, Animals, Astrocytes, Cell Differentiation, DNA-Binding Proteins, Female, Interneurons, Male, Motor Neurons, Mutation, Nerve Tissue Proteins, Neuroglia, Neurons, Oligodendroglia, Rhombencephalon, Spinal Cord, Stem Cells, Transcription Factors, Helix-Loop-Helix Motifs, Mice, Knockout, Homeodomain Proteins, Cell Lineage, Mice, Basic Helix-Loop-Helix Proteins
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