Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells.

During their migration, cerebellar granule cells switch from a tangential to a radial mode of migration. We have previously demonstrated that this involves the transmembrane semaphorin Sema6A. We show here that plexin-A2 is the receptor that controls Sema6A function in migrating granule cells. In plexin-A2-deficient (Plxna2(-/-)) mice, which were generated by homologous recombination, many granule cells remained in the molecular layer, as we saw in Sema6a mutants. A similar phenotype was observed in mutant mice that were generated by mutagenesis with N-ethyl-N-nitrosourea and had a single amino-acid substitution in the semaphorin domain of plexin-A2. We found that this mutation abolished the ability of Sema6A to bind to plexin-A2. Mouse chimera studies further suggested that plexin-A2 acts in a cell-autonomous manner. We also provide genetic evidence for a ligand-receptor relationship between Sema6A and plexin-A2 in this system. Using time-lapse video microscopy, we found that centrosome-nucleus coupling and coordinated motility were strongly perturbed in Sema6a(-/-) and Plxna2(-/-) granule cells. This suggests that semaphorin-plexin signaling modulates cell migration by controlling centrosome positioning

Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome

Hypopigmentation along Blaschko’s lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Item does not contain fulltextBrain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes

Increased LIS1 expression affects human and mouse brain development

10 pages, 7 figures.-- Supplementary information (Suppl. data, 17 pages, and suppl. movies S1-S2) available at: http://www.nature.com/ng/journal/vaop/ncurrent/suppinfo/ng.302_S1.htmlDeletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a 'reverse genomics' approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.The work was supported in part by the Israeli Science Foundation (grant no. 270/04 to O.R. and an equipment grant), the Foundation Jérôme Lejeune, the Minerva Foundation with funding from the Federal German Ministry for Education and Research, German-Israeli collaboration grant Gr-1905, March of Dimes grant 6-FY07-388, collaborative BSF grant 2007081 (to O.R. and J.R.L.), a grant from the Paul Godfrey Research Foundation in Children’s Diseases, the Benoziyo Center for Neurological Diseases, the Kekst Center, the Forcheimer Center, a Weizmann-Pasteur collaborative grant, a research grant from the Michigan Women of Wisdom Fund to support Weizmann Women scientists, support from Maurice Janin, the Jewish Communal Fund, Albert Einstein College of Medicine of Yeshiva University, the David and Fela Shapell Family Center research grant for Genetic Disorders Research, grants DIGESIC-MEC BFU2005-09085 and Ingenio 2010 MEC-CONSOLIDER CSD2007-00023 (to S.M.), support from EU grant LSHG-CT-2004-512003, the Baylor Medical Genetics Laboratories, the Mental Retardation Developmental Disabilities Research Center (HD024064) and a Program Project grant (P01 HD39420) from the National Institute of Child Health and Human Development (to J.R.L.).Peer reviewe