UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.
University of Amsterdam, Swammerdam Institute for Life Sciences, Amsterdam, the Netherlands.
Cell. 2018 May 31;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 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.
导致人类进化中大脑大小扩张的遗传变化一直难以捉摸。Notch 信号通路对于放射状胶质干细胞的增殖至关重要，也是哺乳动物大脑皮层神经元数量的决定因素。我们发现，人类特异性 NOTCH2NL 的三个旁系同源物在放射状胶质细胞中高度表达。功能分析表明，不同的 NOTCH2NL 等位基因通过与 NOTCH 受体直接相互作用，具有增强 Notch 信号的不同效力。与 Notch 信号通路的作用一致，NOTCH2NL 异位表达可延迟神经元祖细胞的分化，而缺失则加速向皮质神经元的分化。此外，NOTCH2NL 基因在 1q21.1 远端缺失/重复综合征中提供了断点，其中重复与大头畸形和自闭症有关，缺失与小头畸形和精神分裂症有关。因此，人类特异性 NOTCH2NL 基因的出现可能导致了更大的人类新皮层的快速进化，同时伴随着 1q21.1 位点基因组稳定性的丧失，并导致反复出现神经发育障碍。
