ZNF335: A Novel Regulator of Stem Cell Proliferation and Cell Fate in the Cerebral Cortex

Though development of the cerebral cortex is of singular importance to human cognition, it remains very poorly understood. Microcephaly, or "small head," is a neurodevelopmental disorder causing significantly reduced cerebral cortex size, and the disease has proved to be a useful model system for elucidating the steps essential for proper cortical development and cognitive function. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation, however, the elucidation of different microcephaly genes with different functions may shed light on previously unidentified key steps of brain development. 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