IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade

Abstract Insulin-like growth factor 1 (IGF-1) is known to have diverse effects on brain structure and function, including the promotion of stem cell proliferation and neurogenesis in the adult dentate gyrus. However, the intracellular pathways downstream of the IGF-1 receptor that contribute to thes...

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Autores principales:	Sajad Mir, Weikang Cai, Shaun W. Carlson, Kathryn E. Saatman, Douglas A. Andres
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e2ae59a77df6443398e78c028a1d3e03
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spelling	oai:doaj.org-article:e2ae59a77df6443398e78c028a1d3e032021-12-02T15:04:52ZIGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade10.1038/s41598-017-03641-92045-2322https://doaj.org/article/e2ae59a77df6443398e78c028a1d3e032017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03641-9https://doaj.org/toc/2045-2322Abstract Insulin-like growth factor 1 (IGF-1) is known to have diverse effects on brain structure and function, including the promotion of stem cell proliferation and neurogenesis in the adult dentate gyrus. However, the intracellular pathways downstream of the IGF-1 receptor that contribute to these diverse physiological actions remain relatively uncharacterized. Here, we demonstrate that the Ras-related GTPase, RIT1, plays a critical role in IGF-1-dependent neurogenesis. Studies in hippocampal neuronal precursor cells (HNPCs) demonstrate that IGF-1 stimulates a RIT1-dependent increase in Sox2 levels, resulting in pro-neural gene expression and increased cellular proliferation. In this novel cascade, RIT1 stimulates Akt-dependent phosphorylation of Sox2 at T118, leading to its stabilization and transcriptional activation. When compared to wild-type HNPCs, RIT1 −/− HNPCs show deficient IGF-1-dependent Akt signaling and neuronal differentiation, and accordingly, Sox2-dependent hippocampal neurogenesis is significantly blunted following IGF-1 infusion in knockout (RIT1 −/− ) mice. Consistent with a role for RIT1 function in the modulation of activity-dependent plasticity, exercise-mediated potentiation of hippocampal neurogenesis is also diminished in RIT1 −/− mice. Taken together, these data identify the previously uncharacterized IGF1-RIT1-Akt-Sox2 signaling pathway as a key component of neurogenic niche sensing, contributing to the regulation of neural stem cell homeostasis.Sajad MirWeikang CaiShaun W. CarlsonKathryn E. SaatmanDouglas A. AndresNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sajad Mir Weikang Cai Shaun W. Carlson Kathryn E. Saatman Douglas A. Andres IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade
description	Abstract Insulin-like growth factor 1 (IGF-1) is known to have diverse effects on brain structure and function, including the promotion of stem cell proliferation and neurogenesis in the adult dentate gyrus. However, the intracellular pathways downstream of the IGF-1 receptor that contribute to these diverse physiological actions remain relatively uncharacterized. Here, we demonstrate that the Ras-related GTPase, RIT1, plays a critical role in IGF-1-dependent neurogenesis. Studies in hippocampal neuronal precursor cells (HNPCs) demonstrate that IGF-1 stimulates a RIT1-dependent increase in Sox2 levels, resulting in pro-neural gene expression and increased cellular proliferation. In this novel cascade, RIT1 stimulates Akt-dependent phosphorylation of Sox2 at T118, leading to its stabilization and transcriptional activation. When compared to wild-type HNPCs, RIT1 −/− HNPCs show deficient IGF-1-dependent Akt signaling and neuronal differentiation, and accordingly, Sox2-dependent hippocampal neurogenesis is significantly blunted following IGF-1 infusion in knockout (RIT1 −/− ) mice. Consistent with a role for RIT1 function in the modulation of activity-dependent plasticity, exercise-mediated potentiation of hippocampal neurogenesis is also diminished in RIT1 −/− mice. Taken together, these data identify the previously uncharacterized IGF1-RIT1-Akt-Sox2 signaling pathway as a key component of neurogenic niche sensing, contributing to the regulation of neural stem cell homeostasis.
format	article
author	Sajad Mir Weikang Cai Shaun W. Carlson Kathryn E. Saatman Douglas A. Andres
author_facet	Sajad Mir Weikang Cai Shaun W. Carlson Kathryn E. Saatman Douglas A. Andres
author_sort	Sajad Mir
title	IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade
title_short	IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade
title_full	IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade
title_fullStr	IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade
title_full_unstemmed	IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade
title_sort	igf-1 mediated neurogenesis involves a novel rit1/akt/sox2 cascade
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e2ae59a77df6443398e78c028a1d3e03
work_keys_str_mv	AT sajadmir igf1mediatedneurogenesisinvolvesanovelrit1aktsox2cascade AT weikangcai igf1mediatedneurogenesisinvolvesanovelrit1aktsox2cascade AT shaunwcarlson igf1mediatedneurogenesisinvolvesanovelrit1aktsox2cascade AT kathrynesaatman igf1mediatedneurogenesisinvolvesanovelrit1aktsox2cascade AT douglasaandres igf1mediatedneurogenesisinvolvesanovelrit1aktsox2cascade
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IGF-1 mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade

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