Microcephaly Gene Links Trithorax and REST/NRSF to Control Neural Stem Cell Proliferation and Differentiation

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Nov 27

PMID 23178126

Citations 83

Authors

Yawei J Yang

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

Soon will be listed here.

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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