A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets
- Diogo S. Castro1,5,6,
- Ben Martynoga1,
- Carlos Parras1,2,
- Vidya Ramesh1,
- Emilie Pacary1,
- Caroline Johnston3,
- Daniela Drechsel1,
- Mélanie Lebel-Potter1,
- Laura Galinanes Garcia1,
- Charles Hunt1,
- Dirk Dolle4,
- Angela Bithell3,
- Laurence Ettwiller4,
- Noel Buckley3 and
- François Guillemot1
- 1Medical Research Council National Institute for Medical Research, Division of Molecular Neurobiology, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom;
- 2CRICM UPMC/Inserm UMR-S 975/CNRS UMR 7225, Hôpital de la Pitié-Salpêtrière, Paris 750013, France;
- 3Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom;
- 4Heidelberg Institute of Zoology, University of Heidelberg, Heidelberg 69120, Germany
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.
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Footnotes
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↵6 Corresponding author.
E-MAIL dscastro{at}igc.gulbenkian.pt; FAX 351-214407970.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.627811.
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Supplemental material is available for this article.
- Received September 13, 2010.
- Accepted March 17, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press