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

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

  • Cell. 2012 Nov 21;151(5):1097-112. doi: 10.1016/j.cell.2012.10.043.
Yawei J Yang 1,  Andrew E Baltus,  Rebecca S Mathew,  Elisabeth A Murphy,  Gilad D Evrony,  Dilenny M Gonzalez,  Estee P Wang,  Christine A Marshall-Walker,  Brenda J Barry,  Jernej Murn,  Antonis Tatarakis,  Muktar A Mahajan,  Herbert H Samuels,  Yang Shi,  Jeffrey A Golden,  Muhammad Mahajnah,  Ruthie Shenhav,  Christopher A Walsh
Affiliations

Affiliation

  • 1 Division of Genetics and Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
PMID: 23178126 DOI: 10.1016/j.cell.2012.10.043
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.

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