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Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis.
Cell ( IF 38.637 ) Pub Date : 2018-05-31 , DOI: 10.1016/j.cell.2018.03.051
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 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.

中文翻译:

人类特定的NOTCH2NL基因影响Notch信号和皮质神经发生。

导致人类进化中大脑大小扩展的遗传变化仍然难以捉摸。Notch信号对于放射状胶质干细胞的增殖至关重要,并且是哺乳动物皮质中神经元数量的决定因素。我们发现人类特定的NOTCH2NL的三个旁系同源物在radial神经胶质细胞中高度表达。功能分析表明,NOTCH2NL的不同等位基因通过直接与NOTCH受体相互作用,具有增强Notch信号传导的能力。与Notch信号传导中的作用一致,NOTCH2NL异位表达延迟了神经元祖细胞的分化,而缺失则加速了向皮层神经元的分化。此外,NOTCH2NL基因提供了1q21.1远端缺失/复制综合征的断点,重复与大头畸形和自闭症相关,而与小头畸形和精神分裂症相关的缺失。因此,人类特异的NOTCH2NL基因的出现可能有助于更大的人类新皮层的快速进化,伴随着在1q21.1基因座的基因组稳定性的丧失和导致复发性神经发育障碍。
更新日期:2018-05-31
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