| Literature DB >> 29856954 |
Ian T Fiddes1, Gerrald A Lodewijk2, Meghan Mooring1, Colleen M Bosworth1, Adam D Ewing1, Gary L Mantalas3, Adam M Novak1, Anouk van den Bout2, Alex Bishara4, Jimi L Rosenkrantz5, Ryan Lorig-Roach1, Andrew R Field3, Maximilian Haeussler1, Lotte Russo2, Aparna Bhaduri6, Tomasz J Nowakowski6, Alex A Pollen6, Max L Dougherty7, Xander Nuttle8, Marie-Claude Addor9, Simon Zwolinski10, Sol Katzman1, Arnold Kriegstein6, Evan E Eichler11, Sofie R Salama5, Frank M J Jacobs12, David Haussler13.
Abstract
Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that 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 into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders.Entities:
Keywords: 1q21.1; Notch signaling; autism; cortical organoids; human evolution; neural stem cells; neurodevelopment; neurodevelopmental disorders; segmental duplications; structural variation
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Year: 2018 PMID： 29856954 PMCID： PMC5986104 DOI： 10.1016/j.cell.2018.03.051
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582