RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Abstract

Edited by Paul E. FraserAdult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy

“…SOX2 is a transcription factor derived from a single exon within an intron of SOX2OT, and its coding sequence lies in the same transcriptional orientation as the lncRNA SOX2OT [12,13]. SOX2 is uniformly expressed in neural stem cells and critical in the development, maintenance, and differentiation of hippocampal stem and progenitor cell populations [30][31][32][33]. Conditional ablation of SOX2 in adult neural progenitor cells impedes activation of pro-neural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newly derived neurons [34].…”

Muscle atrophy‐related myotube‐derived exosomal microRNA in neuronal dysfunction: Targeting both coding and long noncoding RNAs

“…However, other factors, such as the miR‐29b‐3p targeting neuronal differentiation regulators c‐FOS, BCL‐2, RIT1, and LAMC1 that we identified in this study (Figure ), could also be involved. RIT1, a Ras subfamily GTPase, is known to regulate neuronal differentiation via ERK and p38 pathways (Shi et al, ) and neurogenesis via Akt/Sox2 pathway (Mir, Cai, & Andres, ). LAMC1 (laminin C) is an extracellular matrix protein contributing to the adhesion and survival of neural cells undergoing differentiation (Sun et al, ).…”

RIT1 controls actin dynamics via complex formation with RAC1/CDC42 and PAK1

“…In another study, however, oncogenic RIT1 mutants, including p.A77S and p.M90I also found in NS, stimulated phosphorylation of AKT in PC6 cells [ 37 ]. RIT1-dependent AKT activation in adult hippocampal neuronal precursor cells suggested a role of this signaling cascade in neurogenesis [ 63 ]. Taken together, data on AKT activation by RIT1 are controversial, and functional relevance of RIT1-PIK3-AKT signaling may significantly vary between different cell types.…”