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Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord
An-Chi Tien, Hui-Hsin Tsai, Anna V. Molofsky, Martin McMahon, Lynette C. Foo, Aparna Kaul, Joseph D. Dougherty, Nathaniel Heintz, David H. Gutmann, Ben A. Barres, David H. Rowitch


Expansion of astrocyte populations in the central nervous system is characteristic of evolutionarily more complex organisms. However, regulation of mammalian astrocyte precursor proliferation during development remains poorly understood. Here, we used Aldh1L1-GFP to identify two morphologically distinct types of proliferative astrocyte precursors: radial glia (RG) in the ventricular zone and a second cell type we call an ‘intermediate astrocyte precursor’ (IAP) located in the mantle region of the spinal cord. Astrogenic RG and IAP cells proliferated in a progressive ventral-to-dorsal fashion in a tight window from embryonic day 13.5 until postnatal day 3, which correlated precisely with the pattern of active ERK signalling. Conditional loss of BRAF function using BLBP-cre resulted in a 20% decrease in astrocyte production, whereas expression of activated BRAFV600E resulted in astrocyte hyperproliferation. Interestingly, BRAFV600E mitogenic effects in astrocytes were restricted, in part, by the function of p16INK4A-p19ARF, which limited the temporal epoch for proliferation. Together, these findings suggest that astrocyte precursor proliferation involves distinct RG and IAP cells; is subjected to temporal and spatial control; and depends in part on BRAF signalling at early stages of mammalian spinal cord development.


  • Funding

    This work was supported by grants from the National Institute of Neurological Disorders and Stroke [NS059893 to D.H.R. and B.A.B.]; the National Cancer Institute [CA131261 to M.M., U01-CA141549 to D.H.G.]; and the American Medical Resources Foundation [to N.H.]. D.H.R. and N.H. are Howard Hughes Medical Institute Investigators. Deposited in PMC for release after 6 months.

  • Competing interests statement

    The authors declare no competing financial interests.

  • Supplementary material

    Supplementary material available online at http://dev.biologists.org/lookup/suppl/doi:10.1242/dev.077214/-/DC1

  • Accepted April 29, 2012.
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