by- 23 April 2012
Molecular and cellular Biology (2012)
Proneural NEUROG2 (Neurogenin 2, Ngn2) is essential for neuronal commitment, cell cycle withdrawal and neuronal differentiation. Although NEUROG2’s influence on neuronal commitment and differentiation is beginning to be clarified; its role in cell cycle withdrawal remains unknown. We therefore set out to investigate the molecular mechanisms by which NEUROG2 induces cell cycle arrest during spinal neurogenesis. We developed a large scale chick embryo strategy, designed to find gene networks modified at the onset of NEUROG2 expression, and thereby we identified those involved in controlling the cell cycle. NEUROG2 activation leads to a rapid decrease of a subset of cell cycle regulators acting at G1- and S- phases, including CCND1, CCNE1/2 and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as constitutive activator or repressor respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but open the possibility that CCNE2 is also repressed by a direct mechanism. We demonstrated by phenotypic analysis that this rapid repression of cyclins prevents S phase entry of neuronal precursors, thus favouring cell cycle exit. We also showed that cell cycle exit can be uncoupled from neuronal differentiation and that during normal development NEUROG2 is in charge of tightly coordinating these two processes.
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