Human-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis

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

Cell. 2018;173(6):1356-1369.e22. doi: 10.1016/j.cell.2018.03.051

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 three paralogs of human-specific NOTCH2NL are highly
expressed in radial glia. 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 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., Human-specific Notch paralogs are expressed in radial glia, enhance Notch
signaling and impact neuronal differentiation.,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986104/

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