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Development 2011 Oct 01;13819:4267-77. doi: 10.1242/dev.067900.
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Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis.

Ali F , Hindley C , McDowell G , Deibler R , Jones A , Kirschner M , Guillemot F , Philpott A .

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.

PubMed ID: 21852393
PMC ID: PMC3171226
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cdk2 cdknx eef1a1 gapdh neurog1 neurog2 tubb2b
Antibodies: Tubb2b Ab2
Morpholinos: cdknx MO1

Article Images: [+] show captions
References [+] :
Aguado-Llera, The basic helix-loop-helix region of human neurogenin 1 is a monomeric natively unfolded protein which forms a "fuzzy" complex upon DNA binding. 2010, Pubmed