Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube

Nature volume 438, pages 360–363 (2005)Cite this article

Abstract

Astrocytes are the most abundant and functionally diverse glial population in the vertebrate central nervous system (CNS)1. However, the mechanisms underlying astrocyte specification are poorly understood. It is well established that cellular diversification of neurons in the embryo is generated by position-dependent extrinsic signals and combinatorial interactions of transcription factors that direct specific cell fates by suppressing alternative fates2. It is unknown whether a comparable process determines embryonic astrocyte identity. Indeed, astrocyte development is generally thought to take place in a position-independent manner3,4. Here we show multiple functions of Stem cell leukaemia (Scl, also known as Tal1), which encodes a basic helix–loop–helix (bHLH) transcription factor, in the regulation of both astrocyte versus oligodendrocyte cell fate acquisition and V2b versus V2a interneuron cell fate acquisition in the p2 domain of the developing vertebrate spinal cord. Our findings demonstrate a regionally restricted transcriptional programme necessary for astrocyte and V2b interneuron development, with striking parallels to the involvement of SCL in haematopoiesis. They further indicate that acquisition of embryonic glial subtype identity might be regulated by genetic interactions between SCL and the transcription factor Olig2 in the ventral neural tube.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Scl expression in p2 precursors and regulation of V2b interneuron development.
Figure 2: SCL is necessary and sufficient for ASP development and represses OLP.
Figure 3: Cross-antagonistic interactions between SCL and Olig2.
Figure 4: SCL and Olig2 regulate neuronal and glial subtype development in the ventral neural tube.

Similar content being viewed by others

References

  1. Kettenmann, H. & Ransom, B. R. Electrical coupling between astrocytes and between oligodendrocytes studied in mammalian cell cultures. Glia 1, 64–73 (1988)

    Article  CAS  Google Scholar 

  2. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000)

    Article  CAS  Google Scholar 

  3. Ross, S. E., Greenberg, M. E. & Stiles, C. D. Basic helix-loop-helix factors in cortical development. Neuron 39, 13–25 (2003)

    Article  CAS  Google Scholar 

  4. Doetsch, F. The glial identity of neural stem cells. Nature Neurosci. 6, 1127–1134 (2003)

    Article  CAS  Google Scholar 

  5. Alvarez-Buylla, A., Garcia-Verdugo, J. M. & Tramontin, A. D. A unified hypothesis on the lineage of neural stem cells. Nature Rev. Neurosci. 2, 287–293 (2001)

    Article  CAS  Google Scholar 

  6. Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005)

    Article  CAS  Google Scholar 

  7. Nakashima, K. et al. BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc. Natl Acad. Sci. USA 98, 5868–5873 (2001)

    Article  ADS  CAS  Google Scholar 

  8. Hermanson, O., Jepsen, K. & Rosenfeld, M. G. N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419, 934–939 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Song, M. R. & Ghosh, A. FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nature Neurosci. 7, 229–235 (2004)

    Article  Google Scholar 

  10. Nieto, M., Schuurmans, C., Britz, O. & Guillemot, F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401–413 (2001)

    Article  CAS  Google Scholar 

  11. Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of Sonic Hedgehog signalling required for the specification of motor neuron identity. Cell 87, 661–673 (1996)

    Article  CAS  Google Scholar 

  12. Orentas, D. M., Hayes, J. E., Dyer, K. L. & Miller, R. H. Sonic hedgehog signalling is required during the appearance of spinal cord oligodendrocyte precursors. Development 126, 2419–2429 (1999)

    CAS  PubMed  Google Scholar 

  13. Novitch, B. G., Chen, A. I. & Jessell, T. M. Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2. Neuron 31, 773–789 (2001)

    Article  CAS  Google Scholar 

  14. Lu, Q. R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002)

    Article  CAS  Google Scholar 

  15. Zhou, Q. & Anderson, D. J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002)

    Article  CAS  Google Scholar 

  16. Zhou, Y., Yamamoto, M. & Engel, J. D. GATA2 is required for the generation of V2 interneurons. Development 127, 3829–3838 (2000)

    CAS  PubMed  Google Scholar 

  17. Karunaratne, A., Hargrave, M., Poh, A. & Yamada, T. GATA proteins identify a novel ventral interneuron subclass in the developing chick spinal cord. Dev. Biol. 249, 30–43 (2002)

    Article  CAS  Google Scholar 

  18. Thaler, J. P., Lee, S. K., Jurata, L. W., Gill, G. N. & Pfaff, S. L. LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell 110, 237–249 (2002)

    Article  CAS  Google Scholar 

  19. Porcher, C. et al. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86, 47–57 (1996)

    Article  CAS  Google Scholar 

  20. Gering, M., Rodaway, A. R., Gottgens, B., Patient, R. K. & Green, A. R. The SCL gene specifies haemangioblast development from early mesoderm. EMBO J. 17, 4029–4045 (1998)

    Article  CAS  Google Scholar 

  21. Smith, E., Hargrave, M., Yamada, T., Begley, C. G. & Little, M. H. Coexpression of SCL and GATA3 in the V2 interneurons of the developing mouse spinal cord. Dev. Dyn. 224, 231–237 (2002)

    Article  CAS  Google Scholar 

  22. Pringle, N. P. et al. Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains. Development 130, 93–102 (2003)

    Article  CAS  Google Scholar 

  23. Tzeng, S. F. & de Vellis, J. Id1, Id2, and Id3 gene expression in neural cells during development. Glia 24, 372–381 (1998)

    Article  CAS  Google Scholar 

  24. Stolt, C. C. et al. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev. 17, 1677–1689 (2003)

    Article  CAS  Google Scholar 

  25. Mikkola, H. K. et al. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421, 547–551 (2003)

    Article  ADS  CAS  Google Scholar 

  26. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999)

    Article  CAS  Google Scholar 

  27. Bachoo, R. M. et al. Molecular diversity of astrocytes with implications for neurological disorders. Proc. Natl Acad. Sci. USA 101, 8384–8389 (2004)

    Article  ADS  CAS  Google Scholar 

  28. Porcher, C., Liao, E. C., Fujiwara, Y., Zon, L. I. & Orkin, S. H. Specification of hematopoietic and vascular development by the bHLH transcription factor SCL without direct DNA binding. Development 126, 4603–4615 (1999)

    CAS  PubMed  Google Scholar 

  29. Schlaeger, T. M. et al. Decoding hematopoietic specificity in the helix-loop-helix domain of the transcription factor SCL/Tal-1. Mol. Cell. Biol. 24, 7491–7502 (2004)

    Article  CAS  Google Scholar 

  30. Rowitch, D. H. Glial specification in the vertebrate neural tube. Nature Rev. Neurosci. 5, 409–419 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Ligon, T. Schlaeger, M. Goulding and Q. Ma for technical suggestions and for reagents and comments. S.H.O. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by a Center of Excellence Award from NIDDK (to S.H.O.) and grants (to D.H.R.) from NINDS, the NCI and the National Multiple Sclerosis Society. Author Contributions Y.M. and Y.F. contributed equally to this work. Y.F. generated the transgenic mice and performed initial phenotypic analysis. Y.M. performed chick electroporation studies and all neural tube analyses. Y.M., S.H.O. and D.H.R. wrote the paper. All authors discussed the results and commented on the manuscript.

Author information

Author notes

  1. Yuko Muroyama

    Present address: Department of Developmental Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Massachusetts, 02115, Boston, USA

    Yuko Muroyama, Stuart H. Orkin & David H. Rowitch

  2. Howard Hughes Medical Institute and Divisions of Hematology,

    Yuko Fujiwara & Stuart H. Orkin

  3. Division of Newborn Medicine, Children's Hospital, 300 Longwood Avenue, Massachusetts, 02115, Boston, USA

    David H. Rowitch

Authors
  1. Yuko Muroyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuko Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stuart H. Orkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David H. Rowitch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Stuart H. Orkin or David H. Rowitch.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

SCL function regulates embryonic astrogenesis (PDF 341 kb)

Supplementary Figure 2

SCL specifically regulates V2b IN production (Fig. 1) and its initial expression at 10.5 dpc in mouse (Fig. 1) commences beyond the period of pattern formation and early neurogenesis in the ventral spinal cord. (PDF 392 kb)

Supplementary Figure 3

Evidence that SCL functions as transcriptional activator in the embryonic neural tube and indirectly regulates Olig2 expression. (PDF 220 kb)

Supplementary Methods

This file contains additional details of the methods used in this study. (RTF 29 kb)

Supplementary Figure Legends

This file contains text to accompany the above Supplementary Figures. (RTF 8 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muroyama, Y., Fujiwara, Y., Orkin, S. et al. Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube. Nature 438, 360–363 (2005). https://doi.org/10.1038/nature04139

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04139

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing