title: Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.
abstract: Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation.
authors.affiliation: Division of Genetics and Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yawei J
authors.initials: YJ
authors.lastname: Yang
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Baltus
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Mathew
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Gilad D
authors.initials: GD
authors.lastname: Evrony
authors.forename: Dilenny M
authors.initials: DM
authors.lastname: Gonzalez
authors.forename: Estee P
authors.initials: EP
authors.lastname: Wang
authors.forename: Christine A
authors.initials: CA
authors.lastname: Marshall-Walker
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.forename: Jernej
authors.initials: J
authors.lastname: Murn
authors.forename: Antonis
authors.initials: A
authors.lastname: Tatarakis
authors.forename: Muktar A
authors.initials: MA
authors.lastname: Mahajan
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Samuels
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mahajnah
authors.forename: Ruthie
authors.initials: R
authors.lastname: Shenhav
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005260:Female; D055785:Gene Knockdown Techniques; D005804:Genes, Lethal; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C497422:KMT2A protein, human; C466083:ZNF335 protein, human; C577646:Znf335 protein, mouse