Cell cycle regulation of proliferation versus differentiation in the central nervous system

Abstract

Formation of the central nervous system requires a period of extensive progenitor cell proliferation, accompanied or closely followed by differentiation; the balance between these two processes in various regions of the central nervous system gives rise to differential growth and cellular diversity. The correlation between cell cycle lengthening and differentiation has been reported across several types of cell lineage and from diverse model organisms, both in vivo and in vitro. Furthermore, different cell fates might be determined during different phases of the preceding cell cycle, indicating direct cell cycle influences on both early lineage commitment and terminal cell fate decisions. Significant advances have been made in the last decade and have revealed multi-directional interactions between the molecular machinery regulating the processes of cell proliferation and neuronal differentiation. Here, we first introduce the modes of proliferation in neural progenitor cells and summarise evidence linking cell cycle length and neuronal differentiation. Second, we describe the manner in which components of the cell cycle machinery can have additional and, sometimes, cell-cycle-independent roles in directly regulating neurogenesis. Finally, we discuss the way that differentiation factors, such as proneural bHLH proteins, can promote either progenitor maintenance or differentiation according to the cellular environment. These intricate connections contribute to precise coordination and the ultimate division versus differentiation decision.

Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

“…The transcription factor-bound, euchromatic status of these genes would thereby facilitate genome organization on nuclear reconstitution. Testing this hypothesis has been an intractable problem, because it is difficult to uncouple differentiation from proliferation (40)(41)(42).…”

Effects of addictive drugs on adult neural stem/progenitor cells

“…NSPCs initially undergo proliferation, during which symmetric cell divisions expand the progenitor pool, and later switch to differentiation, during which self-renewing NSPCs give rise to their offspring with different lineages and phenotypes [72]. NSPC differentiation is a crucial step in adult neurogenesis as it determines both the rate of newborn cell generation and the fate of mature cells.…”

“…Two key classes of regulatory molecules, Cyclins and Cyclin-dependent kinases, are responsible for the regulation of the cell cycle [134]. Growing evidence indicates there is an association between cell cycle lengths and the modulation of NSPCs [72], agreeing with the findings found with addictive drugs, including opioids, cocaine, methamphetamine and alcohol [39, 69, 79, 82, 95, 98, 125]. Because mitosis is a crucial step of cell proliferation, it is obvious that factors that controlling the cell cycle may also control NSPC proliferation.…”

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

“…Speculations on mechanisms regulating endocrine commitment vs. progenitor maintenance in Neurog3 TA.LO progenitors Several studies show that the length of the G1 phase of the cell cycle can dictate the choice of progenitor maintenance versus lineage specification (Hindley et al 2012;Pauklin and Vallier 2013;Hardwick et al 2015). For Neurog2 in neural progenitors, the low Cdk/high Cdki activity and lengthened G1 keep Neurog2 nonphosphorylated/ underphosphorylated and stable enough to activate neuronal differentiation targets (Ali et al 2011).…”