摘要：SummaryTheNDE1gene encodes a scaffold protein essential for brain development. Although biallelicNDE1loss of function (LOF) causes microcephaly with profound mental retardation,NDE1missense mutations and copy number variations are associated with multiple neuropsychiatric disorders. However, the etiology of the diverse phenotypes resulting fromNDE1aberrations remains elusive. Here we demonstrate Nde1 controls neurogenesis through facilitating H4K20 trimethylation-mediated heterochromatin compaction. This mechanism patterns diverse chromatin landscapes and stabilizes constitutive heterochromatin of neocortical neurons. We demonstrate that NDE1 can undergo dynamic liquid-liquid phase separation, partitioning to the nucleus and interacting with pericentromeric and centromeric satellite repeats. Nde1 LOF results in nuclear architecture aberrations and DNA double-strand breaks, as well as instability and derepression of pericentromeric satellite repeats in neocortical neurons. These findings uncover a pivotal role of NDE1/Nde1 in establishing and protecting neuronal heterochromatin. They suggest that heterochromatin instability predisposes a wide range of brain dysfunction.Graphical abstractDisplay OmittedHighlights•Cortical neurogenesis is coupled with heterochromatin compaction marked by H4K20me3•Nde1 undergoes liquid-liquid phase separation and interacts with heterochromatin•Nde1 mutations impair H4K20me3 during neural progenitor differentiation•Neurons lacking Nde1 derepress heterochromatin and lose nuclear and genomic integrityBiological sciences; Molecular biology; Neuroscience
