CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development

摘要: Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) but suggested to localize nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) cerebral cortical (microcephaly). CHMP1A-mutant cells impaired proliferation, with increased expression INK4A, negative regulator stem cell proliferation. Chromatin immunoprecipitation suggests loss normal INK4A repression by BMI these cells. Morpholino-based knockdown zebrafish chmp1a resulted brain defects resembling those seen after bmi1a bmi1b knockdown, which were partially rescued ortholog further supporting links between BMI1-mediated regulation INK4A. Our results suggest serves critical link cytoplasmic signals modifications proliferation central nervous system progenitor