Neural stem cells (NSCs) are uncommitted cells of the CNS defined by their multipotentiality and ability to self renew. We found these cells to not be present in substantial numbers in the CNS until after embryonic day (E) 10.5 in mouse and E5 in chick. This coincides with the induction of SOX9 in neural cells. Gain- and loss-of-function studies indicated that SOX9 was essential for multipotent NSC formation. Moreover, Sonic Hedgehog was able to stimulate precocious generation of NSCs by inducing Sox9 expression. SOX9 was also necessary for the maintenance of multipotent NSCs, as shown by in vivo fate mapping experiments in the adult subependymal zone and olfactory bulbs. In addition, loss of SOX9 led ependymal cells to adopt a neuroblast identity. These data identify a functional link between extrinsic and intrinsic mechanisms of NSCs specification and maintenance, and establish a central role for SOX9 in the process.
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We thank A. Schedl (INSERM U636, Nice) for the conditional Sox9 mutant mice, A. Nagy (Samuel Lunenfeld Research Institute) for the pCall2 vector, W.C.W. Chan for blastocyst injections and production of Z/Sox9 mice and T. Caspary (Emory University) for the Arl13b antibody. The CMV:cre construct was a gift from S. O'Gorman (Salk Institute). Thank you to S. Guioli, F. Guillemot and L. Reynard for critical reading of the manuscript, to C. Andoniadou for advice and training in the ways of neurosphere cultures, to W. Han Yau in the photographics department at NIMR for help with illustrations, to T. Matabanadzo and other biological services staff at NIMR for help with the mouse colonies and other members of our laboratories for discussion and encouragement. This work was supported by the UK Medical Research Council (U117512772), a US National Institutes of Health (National Institute of Biomedical Imaging and Bioengineering) Quantum Grant (R.L.-B. and C.E.S.), and grants from the Hong Kong Research Grants Council and the Hong Kong University Grants Council Area of Excellence Scheme (S.L.W. and K.S.E.C.).
The authors declare no competing financial interests.
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Scott, C., Wynn, S., Sesay, A. et al. SOX9 induces and maintains neural stem cells. Nat Neurosci 13, 1181–1189 (2010). https://doi.org/10.1038/nn.2646
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