Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.
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.
Pubmed ID: 23178126 RIS Download
Animals | 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