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.
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This work was supported in part by National Institutes of Health Grant R01 NS045103(DAA) and R01 NS072302 (KES) from the NINDS and the Kentucky Spinal Cord and Head Injury Research Trust (Grants 12-1A and 16-1)(DAA) and a Kentucky Lung Cancer Research Grant(DAA).
The authors acknowledge the use of facilities in the University of Kentucky Center for Molecular Medicine Genetic Technologies Core. This core is supported in part by NIH Grant Number P30GM110787.
Mir, Sajad; Cai, Weikang; Carlson, Shaun W.; Saatman, Kathryn E.; and Andres, Douglas A., "IGF-1 Mediated Neurogenesis Involves a Novel RIT1/Akt/Sox2 Cascade" (2017). Molecular and Cellular Biochemistry Faculty Publications. 113.