MRC National Institute for Medical Research, London
Science for Health
Neural stem cells need Sox9
27 September 2010
Scientists at NIMR have discovered that a gene, Sox9, is critical for the properties of stem cells within the nervous system. The research is published in Nature Neuroscience.
The central nervous system (CNS) is made very early in embryos from a sheet of cells termed the neuroepithelium. This sheet grows rapidly to provide the foundation for the very complex structures of the mature brain and spinal cord. Many types of nerve cells (neurons), their supporting cells, termed glia, as well as some cells that give structural support, such as the ependymal cells that line the ventricles (spaces) are found in the mature CNS. All of these different cell types are produced from specialised cells called neural stem cells (NSC).
Charlotte Scott, working in the labs of Robin Lovell-Badge (pictured) in the Division of Stem Cell Biology and Developmental Genetics and James Briscoe in the Division of Developmental Neurobiology, found that NSCs first appeared in the embryonic brain about half way through gestation, at embryonic day 10 in mouse; this corresponds to a 5 week human embryo. In the laboratory, these NSCs can be grown outside of the brain and when stimulated differentiate into neurons and glia. In the brain, in vivo, NSCs can be marked and their fate followed. In specific regions of the brain some NSCs persist into the adult where they continue to produce neurons, to replace those lost naturally, such as those in the olfactory bulbs which are responsible for our sense of smell.
The new research shows that the gene Sox9, which encodes a transcription factor that governs the activity of many other genes, is active in NSCs. In the embryonic CNS a secreted protein, termed Sonic Hedgehog (Shh), communicates between cells and activates Sox9. The activation of Sox9 converts early neuroepithelial cells into cells with all the properties of NSCs. Furthermore, if Sox9 was mutated in NSCs at later embryonic stages or even in the adult brain, they lost their ability to give rise to glia and to self-renew, and instead they were able to form only a few immature neurons.
SOX9 labels neural stem cells (NSC) in the embryo and adult
(a) In the embryo the transcription factors SOX2 (in red) marks proliferating cells and SOX9 (in green) marks NSCs. Many cells contain both SOX2 and SOX9 in the brain and these are responsible for producing the mature neurons and glia of the brain.
(b) In the adult, slowly dividing cells are believed to be the NSCs. These are labelled by BrdU (in red) and all of them contain SOX9 (in green).
Knowing both a critical gene, Sox9, which acts within cells to confer NSC properties, and an external factor, Shh, that turns it on, may aid in attempts to control stem cells within the brain. This could be helpful in the development of therapies for certain types of degenerative disease, such as Alzheimers, or trauma, such as stroke, when it would be desirable to make new neurons; but also in the development of treatments for specific brain tumours where out of control growth of the stem cells is thought to be responsible.
James Briscoe
Original article
Scott, CE; Wynn, SL; Sesay, A; Cruz, C; Cheung, M; Gaviro, M-VG; Booth, S; Gao, B; Cheah, KSE; Lovell-Badge, R and Briscoe, J (2010)
SOX9 induces and maintains neural stem cells
Nature Neuroscience epub ahead of print. Publisher abstract
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