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

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.

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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.

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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.

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

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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)

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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

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