Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis

Publication date: 31 May 2018 Source:Cell, Volume 173, Issue 6 Author(s): 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 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...

Source: Cell - June 1, 2018 Category: Cytology Source Type: research