Cenpj/CPAP regulates progenitor divisions and neuronal migration in the cerebral cortex downstream of Ascl1

Patricia P. Garcez (), Javier Diaz-Alonso, Ivan Crespo-Enriquez, Diogo Castro, Donald Bell and François Guillemot ()
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Patricia P. Garcez: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
Javier Diaz-Alonso: School of Biology and Instituto Universitario de Investigaciones Neuroquímicas (IUIN), Complutense University
Ivan Crespo-Enriquez: King’s College London, Guy’s Tower Wing, Floor 27, London SE1 9RT, UK
Diogo Castro: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
Donald Bell: Confocal and Image Analysis Laboratory, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
François Guillemot: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract The proneural factor Ascl1 controls multiple steps of neurogenesis in the embryonic brain, including progenitor division and neuronal migration. Here we show that Cenpj, also known as CPAP, a microcephaly gene, is a transcriptional target of Ascl1 in the embryonic cerebral cortex. We have characterized the role of Cenpj during cortical development by in utero electroporation knockdown and found that silencing Cenpj in the ventricular zone disrupts centrosome biogenesis and randomizes the cleavage plane orientation of radial glia progenitors. Moreover, we show that downregulation of Cenpj in post-mitotic neurons increases stable microtubules and leads to slower neuronal migration, abnormal centrosome position and aberrant neuronal morphology. Moreover, rescue experiments shows that Cenpj mediates the role of Ascl1 in centrosome biogenesis in progenitor cells and in microtubule dynamics in migrating neurons. These data provide insights into genetic pathways controlling cortical development and primary microcephaly observed in humans with mutations in Cenpj.

Date: 2015
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DOI: 10.1038/ncomms7474

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