Author/Authors :
Yawei J. Yang، نويسنده , , Andrew E. Baltus، نويسنده , , Rebecca S. Mathew، نويسنده , , Elisabeth A. Murphy، نويسنده , , Gilad D. Evrony، نويسنده , , Dilenny M. Gonzalez، نويسنده , , Estee P. Wang، نويسنده , , Christine A. Marshall-Walker، نويسنده , , Brenda J. Barry، نويسنده , , Jernej Murn، نويسنده , , Antonis Tatarakis، نويسنده , , Muktar A. Mahajan، نويسنده , , Herbert H. Samuels، نويسنده , , Yang Shi، نويسنده , , Jeffrey A. Golden، نويسنده , , Muhammad Mahajnah، نويسنده , , Ruthie Shenhav، نويسنده , , Christopher A. Walsh، نويسنده ,
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.
