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

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


  • Yang YJ
  • Baltus AE
  • Mathew RS
  • Murphy EA
  • Evrony GD
  • Gonzalez DM
  • Wang EP
  • Marshall-Walker CA
  • Barry BJ
  • Murn J
  • Tatarakis A
  • Mahajan MA
  • Samuels HH
  • Shi Y
  • Golden JA
  • Mahajnah M
  • Shenhav R
  • Walsh CA



Publication Data

November 21, 2012

Associated Grants

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

Mesh Terms

  • Animals
  • Carrier Proteins
  • Cell Differentiation
  • Cell Proliferation
  • Female
  • Gene Knockdown Techniques
  • Genes, Lethal
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Microcephaly
  • Multiprotein Complexes
  • Myeloid-Lymphoid Leukemia Protein
  • Neural Stem Cells
  • Neurogenesis
  • Nuclear Proteins
  • Repressor Proteins