title: Requirement of mouse BCCIP for neural development and progenitor proliferation.
abstract: Multiple DNA repair pathways are involved in the orderly development of neural systems at distinct stages. The homologous recombination (HR) pathway is required to resolve stalled replication forks and critical for the proliferation of progenitor cells during neural development. BCCIP is a BRCA2 and CDKN1A interacting protein implicated in HR and inhibition of DNA replication stress. In this study, we determined the role of BCCIP in neural development using a conditional BCCIP knock-down mouse model. BCCIP deficiency impaired embryonic and postnatal neural development, causing severe ataxia, cerebral and cerebellar defects, and microcephaly. These development defects are associated with spontaneous DNA damage and subsequent cell death in the proliferative cell populations of the neural system during embryogenesis. With in vitro neural spheroid cultures, BCCIP deficiency impaired neural progenitor's self-renewal capability, and spontaneously activated p53. These data suggest that BCCIP and its anti-replication stress functions are essential for normal neural development by maintaining an orderly proliferation of neural progenitors.
authors.affiliation: The Cancer Institute of New Jersey, Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Huang
authors.forename: Huimei
authors.initials: H
authors.lastname: Lu
authors.forename: Stephany
authors.initials: S
authors.lastname: Liu
authors.forename: Roberto
authors.initials: R
authors.lastname: Droz-Rosario
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000818:Animals; D001259:Ataxia / Q000150:complications / Q000151:congenital / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006130:Growth Disorders / Q000150:complications / Q000151:congenital / Q000235:genetics / Q000473:pathology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009928:Organ Specificity / Q000235:genetics; D004856:Postural Balance / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012678:Sensation Disorders / Q000150:complications / Q000151:congenital / Q000235:genetics / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology
chemical_list: C569563:BCCIP protein, mouse; D018797:Cell Cycle Proteins; D005904:Glial Fibrillary Acidic Protein; C045073:Cre recombinase; D019426:Integrases