Abstract
The adult dentate gyrus continuously generates new neurons that endow the brain with increased plasticity, helping to cope with changing environmental and cognitive demands. The process leading to the birth of new neurons spans several precursor stages and is the result of a coordinated series of fate decisions, which are tightly controlled by extrinsic signals. Many of these signals act through modulation of cell cycle (CC) components, not only to drive proliferation, but also for linage commitment and differentiation. In this review, we provide a comprehensive overview on key CC components and regulators, with emphasis on G1 phase, and analyze their specific functions in precursor cells of the adult hippocampus. We explore their role for balancing quiescence versus self-renewal, which is essential to maintain a lifelong pool of neural stem cells while producing new neurons “on demand.” Finally, we discuss available evidence and controversies on the impact of CC/G1 length on proliferation versus differentiation decisions.
Highlights
Inhibition of CDK4 in precursors isolated from the adult subgranular zone (SGZ) or subventricular zone (SVZ) proportionally increased the number of cells in G1 and forced neuronal differentiation
CDK4 is expressed by virtually all Ki67-positive cells in the adult SGZ, its loss had no effect on CC parameters, proliferation or neurogenesis (Beukelaers et al, 2011)
INK4 family members being the main inhibitors of CDK4/6, their physiological significance in adult neurogenesis appears comparably low, with the exception of p16INK4a that emerged as important regulator of neural stem cells (NSC) self-renewal in the aging brain
Summary
The presence of NSC capable of generating new neurons throughout life provides adult mammals with an exceptional level of brain plasticity. aNSC are multipotent, have the capacity to selfrenew and generate progenitor cells which give rise to neurons that functionally integrate into pre-existing networks (Zhao et al, 2006; Suh et al, 2007; Toni et al, 2008; Zhao et al, 2008; Bonaguidi et al, 2011; Encinas et al, 2011; Mongiat and Schinder, 2011; Pilz et al, 2018). Expression and functional studies suggest that p21cip1 has a predominant role in DNAdamage-induced CC arrest, while p27kip1 inhibits cell growth and maintains cells in a quiescent state, and p57kip2 regulates growth and differentiation (Deng et al, 1995; Nakayama et al, 1996; Zhang et al, 1997; Besson et al, 2008).
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