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

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

doi:10.3389/fnmol.2017.00124

Katya Zelentsova-Levytskyi, Tal Burstyn-Cohen + Show 4 more

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https://doi.org/10.3389/fnmol.2017.00124

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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 p16Ink4a and p19Arf 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.

Highlights

Regulation of Neural stem and progenitor cell (NSPC) proliferation and self-renewal is key for normal development and adult brain homeostasis
We recently reported that the conditional deletion of Pros1 in NSPCs led to a 52 and 57% increase in SVZ and subgranular zone (SGZ) NSPC proliferation, respectively (Zelentsova et al, 2016)
We first assessed the numbers of Sox2+ cells located in the SGZ by immunostaining and found a 50% increase in the numbers of Sox2+ cells confined to the SGZ of Pros1-cKO adult mice, compared to control littermates (Figures 1C–E), suggesting increased numbers of NSPCs

Summary

Introduction

Regulation of Neural stem and progenitor cell (NSPC) proliferation and self-renewal is key for normal development and adult brain homeostasis. Radial NSCs give rise to neurons, astrocytes, and additional NSCs, and are multipotent and self-renewing (Suh et al, 2007; Bonaguidi et al, 2011). They express Nestin, Sox, GFAP, and Vimentin, and are seldom labeled with 5-Bromo-2′deoxyuridine (BrdU), comprising the replication-quiescent population of neural progenitors; QNPs (Garcia et al, 2004; Seri et al, 2004; Suh et al, 2007).

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