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