Journal
DEVELOPMENT
Volume 138, Issue 19, Pages 4267-4277Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.067900
Keywords
Cell cycle; Neuronal differentiation; Ngn2; Phosphorylation; Xenopus
Categories
Funding
- MRC [G0700758]
- MRC DTA
- Cancer Research UK
- Medical Research Council [U117570528]
- National Institute of General Medical Sciences [GM26875]
- Medical Research Council [G0500101, G0800784, MC_U117570528, G0700758, G0800784B] Funding Source: researchfish
- MRC [G0800784, MC_U117570528, G0700758, G0500101] Funding Source: UKRI
Ask authors/readers for more resources
During development of the central nervous system, the transition from progenitor maintenance to differentiation is directly triggered by a lengthening of the cell cycle that occurs as development progresses. However, the mechanistic basis of this regulation is unknown. The proneural transcription factor Neurogenin 2 (Ngn2) acts as a master regulator of neuronal differentiation. Here, we demonstrate that Ngn2 is phosphorylated on multiple serine-proline sites in response to rising cyclin-dependent kinase (cdk) levels. This multi-site phosphorylation results in quantitative inhibition of the ability of Ngn2 to induce neurogenesis in vivo and in vitro. Mechanistically, multi-site phosphorylation inhibits binding of Ngn2 to E box DNA, and inhibition of DNA binding depends on the number of phosphorylation sites available, quantitatively controlling promoter occupancy in a rheostat-like manner. Neuronal differentiation driven by a mutant of Ngn2 that cannot be phosphorylated by cdks is no longer inhibited by elevated cdk kinase levels. Additionally, phosphomutant Ngn2-driven neuronal differentiation shows a reduced requirement for the presence of cdk inhibitors. From these results, we propose a model whereby multi-site cdk-dependent phosphorylation of Ngn2 interprets cdk levels to control neuronal differentiation in response to cell cycle lengthening during development.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available