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Microcephaly Gene Links Trithorax and REST/NRSF to Control Neural Stem Cell Proliferation and Differentiation
Open accessAbstract
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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“In fact, mutant mouse studies demonstrated the essential role of ZNF335 in neuronal differentiation and brain development (Yang et al. 2012).”
From The Human Accelerated Region HAR202 Controls NPAS3 Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Yang et al. 2012
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Metadata
- Authors
- 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.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- New York University (US)
- Brigham and Women's Hospital (US)
- Technion – Israel Institute of Technology (IL)
- Rabin Medical Center (IL)
- Corresponding author
- Walsh, Christopher A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 151
- Issue
- 5
- Pages
- 1097-1112
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3567437
- OpenAlex
- W2161564843
- Cited by
- 176
- References
- 50
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 12 · 2022: 11 · 2021: 11 · 2020: 21 · 2019: 12 · 2018: 17 · 2017: 17 · 2016: 14 · 2015: 14 · 2014: 16 · 2013: 5
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- Elsevier eBooks
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA118487, CA118487)
- National Institute of General Medical Sciences (GM058012, T32GM007753, R01GM071004, R01GM058012, GM071004)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK016636, R01 DK16636)
- National Institute of Neurological Disorders and Stroke (R01 NS35129,, R01NS035129, R01NS032457)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007466)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- microcephaly, Trithorax group proteins, REST/NRSF, H3K4 methylation, neural stem cell proliferation, neurogenesis, neuronal differentiation, centrosome, conditional knockout mice, zinc finger proteins
- MeSH terms
- RE1-Silencing Transcription Factor, Animals, Carrier Proteins, Cell Differentiation, DNA-Binding Proteins, Female, Genes, Lethal, Humans, Male, Microcephaly, Nuclear Proteins, Histone-Lysine N-Methyltransferase, Repressor Proteins, Transcription Factors, Mice, Knockout, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Mice, Myeloid-Lymphoid Leukemia Protein, Neurogenesis, Gene Knockdown Techniques, Neural Stem Cells
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