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

Authors :
Gary L. Mantalas
Lotte Russo
Jimi L. Rosenkrantz
Frank M. J. Jacobs
Anouk van den Bout
Adam D. Ewing
Meghan Mooring
Aparna Bhaduri
Ryan Lorig-Roach
Simon Zwolinski
Gerrald A Lodewijk
Adam M. Novak
Colleen M. Bosworth
David Haussler
Sofie R. Salama
Ian T. Fiddes
Sol Katzman
Alex Bishara
Maximillian Haeussler
Xander Nuttle
Max L. Dougherty
Arnold R. Kriegstein
Tomasz J. Nowakowski
Evan E. Eichler
Andrew R. Field
Marie-Claude Addor
Alex A. Pollen
Publication Year :
2017
Publisher :
Cold Spring Harbor Laboratory, 2017.

Abstract

SummaryGenetic 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....d9e805c4308c4b5f53386c2353f5048c