Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis

Cell. 2018 May 31;173(6):1356-1369.e22. doi: 10.1016/j.cell.2018.03.051.

Ian T Fiddes ¹, Gerrald A Lodewijk ², Meghan Mooring ¹, Colleen M Bosworth ¹, Adam D Ewing ¹, Gary L Mantalas ³, Adam M Novak ¹, Anouk van den Bout ², Alex Bishara ⁴, Jimi L Rosenkrantz ⁵, Ryan Lorig-Roach ¹, Andrew R Field ³, Maximilian Haeussler ¹, Lotte Russo ², Aparna Bhaduri ⁶, Tomasz J Nowakowski ⁶, Alex A Pollen ⁶, Max L Dougherty ⁷, Xander Nuttle ⁸, Marie-Claude Addor ⁹, Simon Zwolinski ¹⁰, Sol Katzman ¹, Arnold Kriegstein ⁶, Evan E Eichler ¹¹, Sofie R Salama ⁵, Frank M J Jacobs ¹², David Haussler ¹³

Affiliations

1 UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.
2 University of Amsterdam, Swammerdam Institute for Life Sciences, Amsterdam, the Netherlands.
3 UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA; Molecular, Cell and Developmental Biology Department, UC Santa Cruz, Santa Cruz, CA, USA.
4 Department of Computer Science, Stanford University, Stanford, CA, USA.
5 UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA; Howard Hughes Medical Institute, UC Santa Cruz, Santa Cruz, CA, USA.
6 Department of Neurology and the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research at the University of California, San Francisco, San Francisco, CA, USA.
7 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
8 Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
9 Service de génétique médicale, Lausanne, Switzerland.
10 Department of Cytogenetics, Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
11 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
12 UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA; University of Amsterdam, Swammerdam Institute for Life Sciences, Amsterdam, the Netherlands. Electronic address: F.M.J.Jacobs@uva.nl.
13 UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA; Howard Hughes Medical Institute, UC Santa Cruz, Santa Cruz, CA, USA. Electronic address: haussler@ucsc.edu.

PMID: 29856954 DOI: 10.1016/j.cell.2018.03.051

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.

Keywords

1q21.1; Notch signaling; autism; cortical organoids; human evolution; neural stem cells; neurodevelopment; neurodevelopmental disorders; segmental duplications; structural variation.

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