Stem Cells. 2017 Mar;35(3):679-693. doi: 10.1002/stem.2522.

Protein S Regulates Neural Stem Cell Quiescence and Neurogenesis.

Zelentsova K1, Talmi Z1, Abboud-Jarrous G1, Sapir T2, Capucha T1, Nassar M1, Burstyn-Cohen T1.
1 The Institute for Dental Sciences, Faculty of Dental Medicine, Hebrew University-Hadassah, Jerusalem, Israel.
2 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.



Neurons are continuously produced in brains of adult mammalian organisms throughout life-a process tightly regulated to ensure a balanced homeostasis. In the adult brain, quiescent Neural Stem Cells (NSCs) residing in distinct niches engage in proliferation, to self-renew and to give rise to differentiated neurons and astrocytes. The mechanisms governing the intricate regulation of NSC quiescence and neuronal differentiation are not completely understood. Here, we report the expression of Protein S (PROS1) in adult NSCs, and show that genetic ablation of Pros1 in neural progenitors increased hippocampal NSC proliferation by 47%. We show that PROS1 regulates the balance of NSC quiescence and proliferation, also affecting daughter cell fate. We identified the PROS1-dependent downregulation of Notch1 signaling to correlate with NSC exit from quiescence. Notch1 and Hes5 mRNA levels were rescued by reintroducing Pros1 into NCS or by supplementation with purified PROS1, suggesting the regulation of Notch pathway by PROS1. Although Pros1-ablated NSCs show multilineage differentiation, we observed a 36% decrease in neurogenesis, coupled with a similar increase in astrogenesis, suggesting PROS1 is instructive for neurogenesis, and plays a role in fate determination, also seen in aged mice. Rescue experiments indicate PROS1 is secreted by NSCs and functions by a NSC-endogenous mechanism. Our study identifies a duple role for PROS1 in stemcell quiescence and as a pro-neurogenic factor, and highlights a unique segregation of increased stem cell proliferation from enhanced neuronal differentiation, providing important insight into the regulation and control of NSC quiescence and differentiation.

KEYWORDS: Neural stem cells; Neurogenesis; Notch; Proliferation; Protein S; Quiescence

The blood anticoagulant Protein S is involved in Neural Stem Cell quiescence and differentiation

Many factors regulate different phases in the life cycle of stem cells. A surprising addition to these factors is Protein S (PROS1), best known as a blood anticoagulant. Researchers discovered that PROS1 which is expressed by embryonic and adult neural stem cells (NSCs) functions to maintain NSC quiescence over proliferation through Notch1 signaling, and also contributes to generating new neurons in the adult hippocampus, necessary for ongoing learning and memory.