The Cyclin-Dependent Kinase Inhibitor p27kip1 Regulates Radial Stem Cell Quiescence and Neurogenesis in the Adult Hippocampus

Abstract

Members of the cyclin-dependent kinase (CDK)-inhibitory protein (CIP)/kinase-inhibitory protein (KIP) family of cyclin-dependent kinase inhibitors regulate proliferation and cell cycle exit of mammalian cells. In the adult brain, the CIP/KIP protein p27 kip1 has been related to the regulation of intermediate progenitor cells located in neurogenic niches. Here, we uncover a novel function of p27 kip1 in the adult hippocampus as a dual regulator of stem cell quiescence and of cell-cycle exit of immature neurons. In vivo, p27 kip1 is detected in radial stem cells expressing SOX2 and in newborn neurons of the dentate gyrus. In vitro, the Cdkn1b gene encoding p27 kip1 is transcriptionally upregulated by quiescence signals such as BMP4. The nuclear accumulation of p27 kip1 protein in adult hippocampal stem cells encompasses the BMP4-induced quiescent state and its overexpression is able to block proliferation. p27 kip1 is also expressed in immature neurons upon differentiation of adult hippocampal stem cell cultures. Loss of p27 kip1 leads to an increase in proliferation and neurogenesis in the adult dentate gyrus, which results from both a decrease in the percentage of radial stem cells that are quiescent and a delay in cell cycle exit of immature neurons. Analysis of animals carrying a disruption in the cyclin-CDK interaction domain of p27 kip1 indicates that the CDK inhibitory function of the protein is necessary to control the activity of radial stem cells. Thus, we report that p27 kip1 acts as a central player of the molecular program that keeps adult hippocampal stem cells out of the cell cycle.

Role and regulation of p27 in neuronal apoptosis

“…; Andreu et al . ), it seems to contribute to neuronal cell death in response to stress like Aβ 42 . Its ability to interact and stabilize Cdk5/cyclin D1 complex plays a critical role in this process as neuronal survival and cell‐cycle suppression‐mediated by Cdk5 is attenuated upon its dissociation from its regulatory partner p35 (Fig.…”

Detection and Phenotypic Characterization of Adult Neurogenesis

“…Also, the differential expression of key cell-cycle protein precursors of different lineages has also been useful in understanding the different kinetics underlying, for example, neural versus oligodendrocytic precursors (Matsumoto et al 2011). Recently, endogenous cell-cycle proteins have also been found in cells in certain stages of adult neurogenesis development, for example, p27 kip1 in neural stem cells (Andreu et al 2014) and cyclin D2 in progenitor cells (Kowalczyk et al 2004). Combination of exogenous thymidine analog administration and endogenous cell-cycle protein detection can corroborate the findings with exogenous markers and provide additional details about cell-cycle kinetics (Lagace et al 2010;Zhang et al 2013).…”

MiR-142-3p Enhances Cell Viability and Inhibits Apoptosis by Targeting CDKN1B and TIMP3 Following Sciatic Nerve Injury

“…However, the expression miR-21 and miR-222 was not significant as much as miR-142-3p in this study, suggesting that they may play roles in different time point after sciatic nerve injury. Another target protein, CDKN1B (p27 kipl ), which is required for quiescent cells to enter cell cycle in many cell types [45], were also reported to be regulated by miRNAs, including miR-194, miR-200, mir-221, miR-24-3p and miR-452[46-50]. Our findings of miR-142-3p regulation of CDKN1B could deepen our knowledge about miRNA regulation and nerve regeneration in further.…”