Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord.
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-p19(ARF), 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.
Department of Pediatrics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Howard Hughes Medical Institute, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
An-Chi
AC
Tien
Hui-Hsin
HH
Tsai
Anna V
AV
Molofsky
Martin
M
McMahon
Lynette C
LC
Foo
Aparna
A
Kaul
Joseph D
JD
Dougherty
Nathaniel
N
Heintz
David H
DH
Gutmann
Ben A
BA
Barres
David H
DH
Rowitch
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D013116:Spinal Cord / Q000166:cytology* / Q000196:embryology
D000444:Aldehyde Dehydrogenase