title: CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development.
abstract: Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells.
authors.affiliation: Department of Medicine, Division of Genetics, Boston Children's Hospital, Massachusetts, USA.
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Ganesh
authors.forename: Maria I
authors.initials: MI
authors.lastname: de Michelena
authors.forename: Hugo
authors.initials: H
authors.lastname: Dias
authors.forename: Kutay D
authors.initials: KD
authors.lastname: Atabay
authors.forename: Katie L
authors.initials: KL
authors.lastname: Kathrein
authors.forename: Hsuan-Ting
authors.initials: HT
authors.lastname: Huang
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Felie
authors.forename: Daniel
authors.initials: D
authors.lastname: Rakiec
authors.forename: Danielle
authors.initials: D
authors.lastname: Gleason
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Hill
authors.forename: Athar N
authors.initials: AN
authors.lastname: Malik
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.forename: Wen-Hann
authors.initials: WH
authors.lastname: Tan
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Glader
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002525:Cerebellar Cortex / Q000254:growth & development / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008040:Genetic Linkage; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D033921:Vesicular Transport Proteins; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: C443709:CHMP1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D056827:Endosomal Sorting Complexes Required for Transport; D033921:Vesicular Transport Proteins; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7