Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny.

中文翻译：

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人类皮层神经元的突触新生需要 SRGAP2-SYNGAP1 交叉抑制的物种特异性平衡


人类特异性 （HS） 基因与大脑进化有关，但它们对人类神经元发育和疾病的影响仍不清楚。在这里，我们研究了 SRGAP2B/C，即祖先突触基因SRGAP2A的两个 HS 基因重复，在小鼠皮层中异种移植的人类皮层锥体神经元 （CPN）。人类 CPN 中 SRGAP2B/C 的下调导致突触发育强烈加速，表明它们需要区分人类突触发生的新生儿。SRGAP2B/C 基因通过降低 SRGAP2A 的突触水平来促进 neoteny，从而增加由主要智力障碍/自闭症谱系障碍 （ID/ASD） 基因编码的 SYNGAP1 蛋白的突触后积累。体内组合功能丧失实验 表明，突触发生的速度是由 SRGAP2A 和 SYNGAP1 之间的相互拮抗决定的，在人类 CPN 中，突触发性为 SRGAP2B/C。因此，HS 基因可以通过调节人类突触新生儿来改变导致 ID/ASD 的基因突变的表型表达。