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Cell. 2012 Nov 21;151(5):1097-112. doi: 10.1016/j.cell.2012.10.043.

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

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1
Division of Genetics and Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.

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.

PMID:
23178126
PMCID:
PMC3567437
DOI:
10.1016/j.cell.2012.10.043
[Indexed for MEDLINE]
Free PMC Article

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