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NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle

NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of... NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G 1 and S Phases of the Cell Cycle Marine Lacomme a , Laurence Liaubet b , Fabienne Pituello a and Sophie Bel-Vialar a a Centre de Biologie du Développement, CNRS UMR5547, Toulouse, France b Laboratoire de Génétique Cellulaire, INRA UMR444, Castanet Tolosan, France ABSTRACT 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 chicken 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 G 1 and S phases, including CCND1, CCNE1/2, and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as the constitutive activator and repressor, respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but opens 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 favoring 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular and Cellular Biology American Society For Microbiology

NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle

NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G1 and S Phases of the Cell Cycle

Molecular and Cellular Biology , Volume 32 (13): 2596 – Jul 1, 2012

Abstract

NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G 1 and S Phases of the Cell Cycle Marine Lacomme a , Laurence Liaubet b , Fabienne Pituello a and Sophie Bel-Vialar a a Centre de Biologie du Développement, CNRS UMR5547, Toulouse, France b Laboratoire de Génétique Cellulaire, INRA UMR444, Castanet Tolosan, France ABSTRACT 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 chicken 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 G 1 and S phases, including CCND1, CCNE1/2, and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as the constitutive activator and repressor, respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but opens 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 favoring 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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Publisher
American Society For Microbiology
Copyright
Copyright © 2012 by the American society for Microbiology.
ISSN
0270-7306
eISSN
1098-5549
DOI
10.1128/MCB.06745-11
pmid
22547683
Publisher site
See Article on Publisher Site

Abstract

NEUROG2 Drives Cell Cycle Exit of Neuronal Precursors by Specifically Repressing a Subset of Cyclins Acting at the G 1 and S Phases of the Cell Cycle Marine Lacomme a , Laurence Liaubet b , Fabienne Pituello a and Sophie Bel-Vialar a a Centre de Biologie du Développement, CNRS UMR5547, Toulouse, France b Laboratoire de Génétique Cellulaire, INRA UMR444, Castanet Tolosan, France ABSTRACT 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 chicken 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 G 1 and S phases, including CCND1, CCNE1/2, and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as the constitutive activator and repressor, respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but opens 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 favoring 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.

Journal

Molecular and Cellular BiologyAmerican Society For Microbiology

Published: Jul 1, 2012

References