AUTHOR=Zelentsova-Levytskyi Katya , Talmi Ziv , Abboud-Jarrous Ghada , Capucha Tal , Sapir Tamar , Burstyn-Cohen Tal 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=10

YEAR=2017

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00124

DOI=10.3389/fnmol.2017.00124

ISSN=1662-5099

ABSTRACT=<p>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 <italic>Pros1</italic> 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<sup>Ink4a</sup> and p19<sup>Arf</sup> to promote NSPC self-renewal in <italic>Pros1</italic>-ablated cells. Rescuing <italic>Pros1</italic> expression restores normal levels of Bmi-1 signaling, and reverts the proliferation and enhanced self-renewal phenotypes observed in <italic>Pros1</italic>-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.</p>