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Cell DOI:10.1016/j.cell.2012.10.043

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

Publication TypeJournal Article
Year of Publication2012
AuthorsYang, 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
Date Published2012/11/21

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.