Human-specific NOTCH -like genes in a region linked to neurodevelopmental disorders affect cortical neurogenesis

Citations Over Time

Abstract

Summary Genetic changes causing dramatic brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number in the mammalian cortex. We find three paralogs of human-specific NOTCH2NL are highly expressed in radial glia cells. Functional analysis reveals different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation. NOTCH2NL genes provide the breakpoints in typical cases of 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. Thus, the emergence of hominin-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger hominin neocortex accompanied by loss of genomic stability at the 1q21. 1 locus and a resulting recurrent neurodevelopmental disorder.

Related Papers

• → Differential interactions between Notch and ID factors control neurogenesis by modulating Hes factor autoregulation(2017)67 cited
• → Neocortex in early mammals and its subsequent variations(2011)58 cited
• → Multiple roles of Ulk4 in neurogenesis and brain function(2017)18 cited
• → Fez1 is layer‐specifically expressed in the adult mouse neocortex(2004)59 cited
• → Embryonic mouse medial neocortex as a model system for studying the radial glial scaffold in fetal human neocortex(2022)3 cited