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

Fahad R Ali,Anna Philpott,Roberta Azzarelli,Laura J A Hardwick

doi:10.1007/s00441-014-1895-8

Fahad R Ali, Anna Philpott + Show 2 more

Open Access

https://doi.org/10.1007/s00441-014-1895-8

Copy DOI

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.

Highlights

During development of the central nervous system (CNS), a period of extensive proliferation is needed to generate the required number of progenitor cells for correct tissue and organ formation
With the use of a cumulative phosphomutant series, Ali et al (2011) have shown that mRNA output from the NeuroD promoter is quantitatively responsive to the number of Ngn2 phosphosites available, allowing Ngn2 to act as a “rheostat” to sense cdk level and duration. This provides a way that the cell cycle kinase environment can directly feed into the DNA-binding activity of a key inducer of differentiation; high cdk activity phosphorylates Ngn2, which is incompatible with the activation of targets driving differentiation, whereas gradual de-phosphorylation of Ngn2 in response to cell cycle lengthening over a critical threshold promotes Ngn2 DNA binding, up-regulating the transcription of specific targets that affect neuronal differentiation (Ali et al 2011)
We have come a long way from the simple observation that cell cycle lengthening accompanies an increased propensity to undergo differentiation, moving towards a more comprehensive understanding of the molecular machinery linking the processes of cell proliferation and neuronal differentiation (Fig. 2)

Summary

Introduction

During development of the central nervous system (CNS), a period of extensive proliferation is needed to generate the required number of progenitor cells for correct tissue and organ formation. Work demonstrated that the lengthening of the cell cycle by the down-regulation of cdk activity is necessary and sufficient for neuronal differentiation, both in vitro in PC12 cells (Dobashi et al 2000) and in vivo in whole embryo mouse culture (Calegari and Huttner 2003).

Results

Conclusion