Microcephaly Gene Links Trithorax and REST/NRSF to Control Neural Stem Cell Proliferation and Differentiation
Name
Yang-2012-Microcephaly Gene Li.pdf
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3.47 MB
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Checksum (MD5)
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Author(s)
Baltus, Andrew E.
Mathew, Rebecca S.
Murphy, Elisabeth A.
Evrony, Gilad D.
Gonzalez, Dilenny M.
Wang, Estee P.
Marshall-Walker, Christine A.
Barry, Brenda J.
Murn, Jernej
Tatarakis, Antonis
Date Issued
November 2012
Journal
Cell
Publisher
Elsevier
Citation
Yang, Yawei J., Andrew E. Baltus, Rebecca S. Mathew, Elisabeth A. Murphy, Gilad D. Evrony, Dilenny M. Gonzalez, Estee P. Wang, et al. “Microcephaly Gene Links Trithorax and REST/NRSF to Control Neural Stem Cell Proliferation and Differentiation.” Cell 151, no. 5 (November 2012): 1097–1112. © 2012 Elsevier Inc.
Version
Final published version
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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1016/j.cell.2012.10.043
