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The balance between neural stem cell proliferation and neuronal differentiation is paramount for the appropriate development of the nervous system. Sonic hedgehog (Shh) is known to sequentially promote cell proliferation and specification of neuronal phenotypes, but the signaling mechanisms responsible for the developmental switch from mitogenic to neurogenic have remained unclear. Here, we show that Shh enhances Ca 2+ activity at the neural cell primary cilium of developing Xenopus laevis embryos through Ca 2+ influx via transient receptor potential cation channel subfamily C member 3 (TRPC3) and release from intracellular stores in a developmental stage-dependent manner. This ciliary Ca 2+ activity in turn antagonizes canonical, proliferative Shh signaling in neural stem cells by down-regulating Sox2 expression and up-regulating expression of neurogenic genes, enabling neuronal differentiation. These discoveries indicate that the Shh-Ca 2+ -dependent switch in neural cell ciliary signaling triggers the switch in Shh action from canonical-mitogenic to neurogenic. The molecular mechanisms identified in this neurogenic signaling axis are potential targets for the treatment of brain tumors and neurodevelopmental disorders.
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Review
Ion channels are expressed throughout nervous system development. The type and diversity of conductances and gating mechanisms vary at different developmental stages and with the progressive maturational status of neural cells. The variety of ion channels allows for distinct signaling mechanisms in developing neural cells that in turn regulate the needed cellular processes taking place during each developmental period. These include neural cell proliferation and neuronal differentiation, which are crucial for developmental events ranging from the earliest steps of morphogenesis of the neural tube through the establishment of neuronal circuits. Here, we compile studies assessing the ontogeny of ionic currents in the developing nervous system. We then review work demonstrating a role for ion channels in neural tube formation, to underscore the necessity of the signaling downstream ion channels even at the earliest stages of neural development. We discuss the function of ion channels in neural cell proliferation and neuronal differentiation and conclude with how the regulation of all these morphogenetic and cellular processes by electrical activity enables the appropriate development of the nervous system and the establishment of functional circuits adapted to respond to a changing environment.
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- Award ID(s):
- 1754340
- PAR ID:
- 10148317
- Date Published:
- Journal Name:
- Frontiers in molecular neuroscience
- Volume:
- 13
- Issue:
- 62
- ISSN:
- 1662-5099
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fnmol.2020.00062
