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Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.

Cell | 2012

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.

Pubmed ID: 23178126 RIS Download

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Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM071004
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007753
  • Agency: NCI NIH HHS, United States
    Id: R01 CA118487
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK016636
  • Agency: NIGMS NIH HHS, United States
    Id: GM058012
  • Agency: NICHD NIH HHS, United States
    Id: T32 HD007466
  • Agency: NIGMS NIH HHS, United States
    Id: T32GM007753
  • Agency: NIGMS NIH HHS, United States
    Id: GM071004
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS032457
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS35129
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK16636
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS035129
  • Agency: NCI NIH HHS, United States
    Id: CA118487
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM058012

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Gene Expression Omnibus (GEO) (tool)

RRID:SCR_007303

Functional genomics data repository supporting MIAME-compliant data submissions. Includes microarray-based experiments measuring the abundance of mRNA, genomic DNA, and protein molecules, as well as non-array-based technologies such as serial analysis of gene expression (SAGE) and mass spectrometry proteomic technology. Array- and sequence-based data are accepted. Collection of curated gene expression DataSets, as well as original Series and Platform records. The database can be searched using keywords, organism, DataSet type and authors. DataSet records contain additional resources including cluster tools and differential expression queries.

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