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

Yang Y.J., Baltus A.E., Mathew R.S., Murphy E.A., Evrony G.D., Gonzalez D.M., Wang E.P., Marshall-Walker C.A., Barry B.J., Murn J., Tatarakis A., Mahajan M.A., Samuels H.H., Shi Y., Golden J.A., Mahajnah M., Shenhav R., Walsh C.A.

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.

Cell 151:1097-1112(2012) [PubMed] [Europe PMC]

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