p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis

Abstract

Throughout life, neural stem cells (NSCs) in the adult hippocampus persistently generate new neurons that modify the neural circuitry. Adult NSCs constitute a relatively quiescent cell population but can be activated by extrinsic neurogenic stimuli. However, the molecular mechanism that controls such reversible quiescence and its physiological significance have remained unknown. Here, we show that the cyclin-dependent kinase inhibitor p57 kip2 (p57) is required for NSC quiescence. In addition, our results suggest that reduction of p57 protein in NSCs contributes to the abrogation of NSC quiescence triggered by extrinsic neurogenic stimuli such as running. Moreover, deletion of p57 in NSCs initially resulted in increased neurogenesis in young adult and aged mice. Long-term p57 deletion, on the contrary, led to NSC exhaustion and impaired neurogenesis in aged mice. The regulation of NSC quiescence by p57 might thus have important implications for the short-term (extrinsic stimuli-dependent) and long-term (age-related) modulation of neurogenesis.

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion

“…Maintaining quiescence requires the expression of cell cycle inhibitors and the downregulation of genes encoding proteins involved in cell cycle progression. Different inhibitors of cyclin-dependent kinases (CDKs), including p57, p27, and p21, are expressed in quiescent NSCs and are required to avoid premature NSC exhaustion [50,96]. Likewise, the chromatin remodeling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) has also been demonstrated to be crucial for NSC pool maintenance.…”

“…An imbalance between a quiescent and an activated state with loss of quiescence can cause a disequilibrium, eventually leading to the premature depletion of NSC pool [96,97]. …”

Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest

“…The recent identification of the role of p57 in the maintenance of quiescent hematopoietic (Matsumoto et al, 2011), neural (Furutachi et al, 2013) and lung (Zacharek et al, 2011) stem cells indicates that p57, along with other CDKIs, is important for stem cell function. Whether such a regulatory mechanism for CDKI expression is redeployed in other systems remains to be investigated.…”

Maternal–fetal conflict, genomic imprinting and mammalian vulnerabilities to cancer

“…IGF2 has been implicated in self-renewal and CDKN1C in quiescence of stem cells [101 -104]. H19 (a MEG) counters the efforts of IGF2 to activate stem cells by release of a microRNA that suppresses the receptor through which IGF-II signals [104]. The multiple roles of imprinted genes in the dynamics of stem cell populations have been characterized as an Imprinted Gene Network (IGN) [105][106][107].…”