title: Novel embryonic neuronal migration and proliferation defects in Dcx mutant mice are exacerbated by Lis1 reduction.
abstract: Heterozygous LIS1 mutations and males with loss of the X-linked DCX result in lissencephaly, a neuronal migration defect. LIS1 regulates nuclear translocation and mitotic division of neural progenitor cells, while the role of DCX in cortical development remains poorly understood. Here, we uncovered novel neuronal migration and proliferation defects in the Dcx mutant embryonic brains. Although cortical organization was fairly well preserved, Dcx(ko/Y) neurons displayed defective migration velocities similar to Lis1(+/ko) neurons when characterized by time-lapse video-microscopy of embryonic cortical slices. Dcx(ko/Y) migrating neurons displayed novel multidirectional movements with abnormal morphology and increased branching. Surprisingly, Dcx(ko/Y) radial glial cells displayed spindle orientation abnormalities similar to Lis1(+/ko) cells that in turn lead to moderate proliferation defects both in vivo and in vitro. We found functional genetic interaction of the two genes, with the combined effects of Lis1 haploinsufficiency and Dcx knock-out leading to more severe neuronal migration and proliferation phenotypes in the Lis1(+/ko);Dcx(ko/Y) male double mutant compared with the single mutants, resulting in cortical disorganization and depletion of the progenitor pool. Thus, we provide definitive evidence for a critical role for Dcx in neuronal migration and neurogenesis, as well as for the in vivo genetic interaction of the two genes most commonly involved in human neuronal migration defects.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California 94143-0794, USA.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Pramparo
authors.forename: Yong Ha
authors.initials: YH
authors.lastname: Youn
authors.forename: Jessica
authors.initials: J
authors.lastname: Yingling
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D048430:Cell Shape / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000002:abnormalities / Q000166:cytology; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D009421:Nervous System Malformations / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics*; D009924:Organ Culture Techniques; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse