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

Yawei J. Yang | Zendy; Andrew E. Baltus | Zendy; Rebecca S. Mathew | Zendy; Elisabeth A. Murphy | Zendy; Gilad D. Evrony | Zendy; Dilenny M. Gonzalez | Zendy; Estee P. Wang | Zendy; Christine A. Marshall-Walker | Zendy; Brenda J. Barry | Zendy; Jernej Murn | Zendy; Antonis Tatarakis | Zendy; MaryAnn Mahajan | Zendy; Herbert H. Samuels | Zendy; Yang Shi | Zendy; Jeffrey A. Golden | Zendy; Muhammad Mahajnah | Zendy; Ruthie Shenhav | Zendy; Christopher A. Walsh | Zendy

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

Author(s) -

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,

MaryAnn Mahajan,

Herbert H. Samuels,

Yang Shi,

Jeffrey A. Golden,

Muhammad Mahajnah,

Ruthie Shenhav,

Christopher A. Walsh

Publication year - 2012

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2012.10.043

Subject(s) - biology , microcephaly , neurogenesis , neural stem cell , cellular differentiation , cell fate determination , neural cell , genetics , progenitor cell , neural development , gene , microbiology and biotechnology , stem cell , cell , transcription factor

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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