Protein S Negatively Regulates Neural Stem Cell Self-Renewal through Bmi-1 Signaling

Frontiers in Molecular Neuroscience
Katya Zelentsova-LevytskyiTal Burstyn-Cohen

Abstract

Revealing the molecular mechanisms underlying neural stem cell self-renewal is a major goal toward understanding adult brain homeostasis. The self-renewing potential of neural stem and progenitor cells (NSPCs) must be tightly regulated to maintain brain homeostasis. We recently reported the expression of Protein S (PROS1) in adult hippocampal NSPCs, and revealed its role in regulation of NSPC quiescence and neuronal differentiation. Here, we investigate the effect of PROS1 on NSPC self-renewal and show that genetic ablation of Pros1 in neural progenitors increased NSPC self-renewal by 50%. Mechanistically, we identified the upregulation of the polycomb complex protein Bmi-1 and repression of its downstream effectors p16(Ink4a) and p19(Arf) to promote NSPC self-renewal in Pros1-ablated cells. Rescuing Pros1 expression restores normal levels of Bmi-1 signaling, and reverts the proliferation and enhanced self-renewal phenotypes observed in Pros1-deleted cells. Our study identifies PROS1 as a novel negative regulator of NSPC self-renewal. We conclude PROS1 is instructive for NSPC differentiation by negatively regulating Bmi-1 signaling in adult and embryonic neural stem cells.

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Citations

Oct 23, 2019·Disease Markers·Giacomo TondoCristoforo Comi
Nov 30, 2019·Cell Communication and Signaling : CCS·Tal Burstyn-Cohen, Avi Maimon
Jul 30, 2020·Cell Stem Cell·Paloma Navarro NegredoAnne Brunet

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Methods Mentioned

BETA
genotyping
PCR

Software Mentioned

STEP
GTP
ImageJ
FlowJo

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