title: VIP blockade leads to microcephaly in mice  via disruption of Mcph1-Chk1 signaling.
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.
authors: Inserm, U676, Paris, France.
authors: Sandrine
authors: S
authors: Passemard
authors: Vincent
authors: V
authors: El Ghouzzi
authors: Hala
authors: H
authors: Nasser
authors: Catherine
authors: C
authors: Verney
authors: Guilan
authors: G
authors: Vodjdani
authors: Adrien
authors: A
authors: Lacaud
authors: Sophie
authors: S
authors: Lebon
authors: Marc
authors: M
authors: Laburthe
authors: Patrick
authors: P
authors: Robberecht
authors: Jeannette
authors: J
authors: Nardelli
authors: Shyamala
authors: S
authors: Mani
authors: Alain
authors: A
authors: Verloes
authors: Pierre
authors: P
authors: Gressens
authors: Vincent
authors: V
authors: Lelièvre
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008831:Microcephaly / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C547654:MCPH1 protein, mouse; D014660:Vasoactive Intestinal Peptide; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse