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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
JournalCell
Volume151
Issue5
Pages1097-112
Date Published2012 Nov 21
ISSN1097-4172
KeywordsAnimals, Carrier Proteins, Cell Differentiation, Cell Proliferation, Female, Gene Knockdown Techniques, Genes, Lethal, Histone-Lysine N-Methyltransferase, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Microcephaly, Multiprotein Complexes, Myeloid-Lymphoid Leukemia Protein, Neural Stem Cells, Neurogenesis, Nuclear Proteins, Repressor Proteins
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(12)01338-4
DOI10.1016/j.cell.2012.10.043
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23178126?dopt=Abstract

Alternate JournalCell
PubMed ID23178126
PubMed Central IDPMC3567437
Grant ListR01 NS032457 / NS / NINDS NIH HHS / United States
R01 NS35129 / NS / NINDS NIH HHS / United States
R01 GM071004 / GM / NIGMS NIH HHS / United States
R01 DK16636 / DK / NIDDK NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 CA118487 / CA / NCI NIH HHS / United States
R01 DK016636 / DK / NIDDK NIH HHS / United States
R01 NS035129 / NS / NINDS NIH HHS / United States
CA118487 / CA / NCI NIH HHS / United States
R01 GM058012 / GM / NIGMS NIH HHS / United States
GM058012 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
T32 HD007466 / HD / NICHD NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
GM071004 / GM / NIGMS NIH HHS / United States