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.

Fig. 1

Representation of the cell cycle. Cell cycle progression is driven by the sequential activation and deactivation of a series of cyclin/cyclin-dependent kinase (cdk) complexes, which are further controlled by cyclin-dependent kinase inhibitors. The decision to divide or differentiate is typically made in early G1 phase, prior to the restriction point (R). Commitment to differentiate is accompanied by transition into G0 phase. Conversely, progression through R commits the cell to at least one more round of cell division

Fig. 2

Possible modes of interaction between cell cycle lengthening/exit and differentiation in the nervous system. a Cell cycle and differentiation are independently regulated (e.g. Lacomme et al. 2012). b Induction of cell cycle lengthening and exit promotes differentiation (e.g. Calegari and Huttner 2003). c Initiation of differentiation results in cell cycle exit (e.g. Farah et al. 2000). d Cell cycle lengthening and exit are co-ordinated with differentiation by dual actions of core components of the cell cycle and differentiation machinery (e.g. Ali et al. ; McGarry and Kirschner ; Kroll et al. ; Vernon et al. 2003). Figure adapted from Ohnuma et al. (2001)