VIP blockade leads to microcephaly in mice via disruption of Mcph1-Chk1 signaling

Passemard, Sandrine and El Ghouzzi, Vincent and Nasser, Hala and Verney, Catherine and Vodjdani, Guilan and Lacaud, Adrien and Lebon, Sophie and Laburthe, Marc and Robberecht, Patrick and Nardelli, Jeannette and Mani, Shyamala and Verloes, Alain and Gressens, Pierre and Lelievre, Vincent (2011) VIP blockade leads to microcephaly in mice via disruption of Mcph1-Chk1 signaling. In: Journal of Clinical Investigation, 121 (8). pp. 3072-3087.

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Abstract

Autosomal recessive primary microcephaly (MCPH) is a genetic disorder that causes a reduction of cortical outgrowth without severe interference with cortical patterning. It is associated with mutations in a number of genes encoding protein involved in mitotic spindle formation and centrosomal activities or cell cycle control. We have shown previously that blocking vasoactive intestinal peptide (VIP) during gestation in mice by using a VIP antagonist (VA) results in microcephaly. Here, we have shown that the cortical abnormalities caused by prenatal VA administration mimic the phenotype described in MCPH patients and that VIP blockade during neurogenesis specifically disrupts Mcph1 signaling. VA administration reduced neuroepithelial progenitor proliferation by increasing cell cycle length and promoting cell cycle exit and premature neuronal differentiation. Quantitative RT-PCR and Western blot showed that VA downregulated Mcph1. Inhibition of Mcph1 expression led to downregulation of Chk1 and reduction of Chk1 kinase activity. The inhibition of Mcph1 and Chk1 affected the expression of a specific subset of cell cycle-controlling genes and turned off neural stem cell proliferation in neurospheres. Furthermore, in vitro silencing of either Mcph1 or Chk1 in neurospheres mimicked VA-induced inhibition of cell proliferation. These results demonstrate that VIP blockade induces microcephaly through Mcph1 signaling and suggest that VIP/Mcph1/Chk1 signaling is key for normal cortical development.

Item Type:	Journal Article
Publication:	Journal of Clinical Investigation
Publisher:	American Society for Clinical Investigation
Additional Information:	Copyright of this article belongs to American Society for Clinical Investigation.
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience
Date Deposited:	30 Aug 2011 05:35
Last Modified:	30 Aug 2011 05:35
URI:	http://eprints.iisc.ac.in/id/eprint/40337

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