RESUMO
Neural stem cells (NSCs) reside in specialized niches in the adult mammalian brain, including the subventricular zone and the dentate gyrus, which act to control NSC behavior. Among other cell types within these niches, NSCs are found in close proximity to blood vessels. We carried out an analysis of the interaction between endothelial cells and NSCs, and show that betacellulin (BTC), a member of the EGF family and one of several signaling molecules made by the former, induces NSC proliferation and prevents spontaneous differentiation in culture. When infused into the lateral ventricle, BTC induces expansion of NSCs and neuroblasts, and promotes neurogenesis in the olfactory bulb and dentate gyrus, whereas specific blocking antibodies reduce the number of stem/progenitor cells. BTC-null mice are less able to regenerate neuroblast numbers compared with WT littermates following depletion of proliferating cells using cytosine-ß-d-arabinofuranoside. BTC acts via both the EGF receptor, located on NSCs, and ErbB4, located on neuroblasts, with the latter explaining why its effects are distinct from those of EGF itself. Our results suggest that BTC could be a good candidate to aid regenerative therapies.
Assuntos
Proliferação de Células , Células Endoteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Transdução de Sinais/fisiologia , Animais , Betacelulina , Western Blotting , Linhagem Celular , Receptores ErbB/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Microscopia Confocal , Células-Tronco Neurais/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-4RESUMO
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.
