Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis

Abstract

<p id="P1">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 <i>NOTCH2NL</i> are highly expressed in radial glia. Functional analysis reveals different alleles of <i>NOTCH2NL</i> have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, <i>NOTCH2NL</i> ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, <i>NOTCH2NL</i> 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 <i>NOTCH2NL</i> 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. </p><p id="P2">Human-specific Notch paralogs are expressed in radial glia, enhance Notch signaling and impact neuronal differentiation. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/41b8ff75-e307-452f-a40c-96618b86c27b/PubMedCentral/image/nihms955026u1.jpg"/> </div> </p>