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

Passemard, Sandrine; Ghouzzi, Vincent El; Nasser, Hala; Verney, Catherine; Vodjdani, Guilan; Lacaud, Adrien; Lebon, Sophie; Laburthe, Marc; Robberecht, Patrick; Nardelli, Jeannette; Mani, Shyamala; Verloes, Alain; Gressèns, Pierre; Lelièvre, Vincent

doi:10.1172/jci43824

Cited by 25 publications

(17 citation statements)

References 86 publications

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“…In fact, two of the down-stream genes regulated by MCPH1 , p73 and cyclinE1 , were reported to be associated with sex dimorphism during germ line development [43,44], suggesting that the regulation of MCPH1 on brain development may differ between males and females. Taken together, the strengthened transactivation effect of human MCPH1 on these down-stream genes may contribute to the greatly enlarged neuro-progenitor pool in the human brain during neurogenesis, which is in line with recent studies that suggest MCPH1 ’s functional role in neuro-progenitor cells through the Chk1-Cdc25-Cdk1 pathway [45,46]. …”

Section: Discussionsupporting

confidence: 80%

Functional divergence of the brain-size regulating gene MCPH1during primate evolution and the origin of humans

Shi

Lin

et al. 2013

BMC Biol

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BackgroundOne of the key genes that regulate human brain size, MCPH1 has evolved under strong Darwinian positive selection during the evolution of primates. During this evolution, the divergence of MCPH1 protein sequences among primates may have caused functional changes that contribute to brain enlargement.ResultsTo test this hypothesis, we used co-immunoprecipitation and reporter gene assays to examine the activating and repressing effects of MCPH1 on a set of its down-stream genes and then compared the functional outcomes of a series of mutant MCPH1 proteins that carry mutations at the human- and great-ape-specific sites. The results demonstrate that the regulatory effects of human MCPH1 and rhesus macaque MCPH1 are different in three of eight down-stream genes tested (p73, cyclinE1 and p14ARF), suggesting a functional divergence of MCPH1 between human and non-human primates. Further analyses of the mutant MCPH1 proteins indicated that most of the human-specific mutations could change the regulatory effects on the down-stream genes. A similar result was also observed for one of the four great-ape-specific mutations.ConclusionsCollectively, we propose that during primate evolution in general and human evolution in particular, the divergence of MCPH1 protein sequences under Darwinian positive selection led to functional modifications, providing a possible molecular mechanism of how MCPH1 contributed to brain enlargement during primate evolution and human origin.

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Section: Discussionsupporting

confidence: 80%

Functional divergence of the brain-size regulating gene MCPH1during primate evolution and the origin of humans

Shi

Lin

et al. 2013

BMC Biol

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“…The protein Microcephalin or MCPH1 is a case in point. MCPH1 is implicated in chromatin remodeling by virtue of its interaction with the SWI/SNF complex (15), in signaling programs via its association with Chk1 among other proteins (11,(29)(30)(31)(32), and aids the DNA repair process by interacting with BRCA2 (33) and Condensin II (34,35). Because of its involvement in multiple processes that converge to maintain genomic integrity, MCPH1 has been termed a "guardian of the genome" (13).…”

Section: Resultsmentioning

confidence: 99%

Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1

Singh¹,

Basnet

Wiltshire

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tyr142, the C-terminal amino acid of histone variant H2A.X is phosphorylated by WSTF (Williams-Beuren syndrome transcription factor), a component of the WICH complex (WSTF-ISWI chromatin-remodeling complex), under basal conditions in the cell. In response to DNA double-strand breaks (DSBs), H2A.X is instantaneously phosphorylated at Ser139 by the kinases ATM and ATR and is progressively dephosphorylated at Tyr142 by the Eya1 and Eya3 tyrosine phosphatases, resulting in a temporal switch from a postulated diphosphorylated (pSer139, pTyr142) to monophosphorylated (pSer139) H2A.X state. How mediator proteins interpret these two signals remains a question of fundamental interest. We provide structural, biochemical, and cellular evidence that Microcephalin (MCPH1), an early DNA damage response protein, can read both modifications via its tandem BRCA1 C-terminal (BRCT) domains, thereby emerging as a versatile sensor of H2A.X phosphorylation marks. We show that MCPH1 recruitment to sites of DNA damage is linked to both states of H2A.X.

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“…Despite the lack of experimental evidence, we can reasonably suppose that changes observed in the composition of the cerebrospinal fluid during brain development can modulate this interplay and eventually influence the transition from NECs to RGCs. In addition, the proliferation of neural progenitors appears to be influenced by extrinsic factors, such as the Vaso-Intestinal-Peptide (VIP) (Passemard et al, 2011), and by miRNAs (Arcila et al, 2014; Ghosh et al, 2014). …”

Section: Neurogenic Phases In the Developing Neocortexmentioning

confidence: 99%

Cellular and molecular introduction to brain development

Jiang

Nardelli

2016

Neurobiology of Disease

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138

118

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Advances in the study of brain development over the last decades, especially recent findings regarding the evolutionary expansion of the human neocortex, and large-scale analyses of the proteome/transcriptome in the human brain, have offered novel insights into the molecular mechanisms guiding neural maturation, and the pathophysiology of multiple forms of neurological disorders. As a preamble to reviews of this issue, we provide an overview of the cellular, molecular and genetic bases of brain development with an emphasis on the major mechanisms associated with landmarks of normal neural development in the embryonic stage and early postnatal life, including neural stem/progenitor cell proliferation, cortical neuronal migration, evolution and folding of the cerebral cortex, synaptogenesis and neural circuit development, gliogenesis and myelination. We will only briefly depict developmental disorders that result from perturbations of these cellular or molecular mechanisms, and the most common perinatal brain injuries that could disturb normal brain development.

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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 out-

Cited by 25 publications

References 86 publications

Functional divergence of the brain-size regulating gene MCPH1during primate evolution and the origin of humans

Functional divergence of the brain-size regulating gene MCPH1during primate evolution and the origin of humans

Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1

Cellular and molecular introduction to brain development

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