title: A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets.
abstract: Proneural genes such as Ascl1 are known to promote cell cycle exit and neuronal differentiation when expressed in neural progenitor cells. The mechanisms by which proneural genes activate neurogenesis--and, in particular, the genes that they regulate--however, are mostly unknown. We performed a genome-wide characterization of the transcriptional targets of Ascl1 in the embryonic brain and in neural stem cell cultures by location analysis and expression profiling of embryos overexpressing or mutant for Ascl1. The wide range of molecular and cellular functions represented among these targets suggests that Ascl1 directly controls the specification of neural progenitors as well as the later steps of neuronal differentiation and neurite outgrowth. Surprisingly, Ascl1 also regulates the expression of a large number of genes involved in cell cycle progression, including canonical cell cycle regulators and oncogenic transcription factors. Mutational analysis in the embryonic brain and manipulation of Ascl1 activity in neural stem cell cultures revealed that Ascl1 is indeed required for normal proliferation of neural progenitors. This study identified a novel and unexpected activity of the proneural gene Ascl1, and revealed a direct molecular link between the phase of expansion of neural progenitors and the subsequent phases of cell cycle exit and neuronal differentiation.
authors.affiliation: Medical Research Council National Institute for Medical Research, Division of Molecular Neurobiology, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. dscastro@igc.gulbenkian.pt
authors.forename: Diogo S
authors.initials: DS
authors.lastname: Castro
authors.forename: Ben
authors.initials: B
authors.lastname: Martynoga
authors.forename: Carlos
authors.initials: C
authors.lastname: Parras
authors.forename: Vidya
authors.initials: V
authors.lastname: Ramesh
authors.forename: Emilie
authors.initials: E
authors.lastname: Pacary
authors.forename: Caroline
authors.initials: C
authors.lastname: Johnston
authors.forename: Daniela
authors.initials: D
authors.lastname: Drechsel
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lebel-Potter
authors.forename: Laura Galinanes
authors.initials: LG
authors.lastname: Garcia
authors.forename: Charles
authors.initials: C
authors.lastname: Hunt
authors.forename: Dirk
authors.initials: D
authors.lastname: Dolle
authors.forename: Angela
authors.initials: A
authors.lastname: Bithell
authors.forename: Laurence
authors.initials: L
authors.lastname: Ettwiller
authors.forename: Noel
authors.initials: N
authors.lastname: Buckley
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis; D011247:Pregnancy; D013687:Telencephalon / Q000166:cytology* / Q000196:embryology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C499317:Ascl1 protein, mouse