The human KCTD13 gene is located within the 16p11.2 locus and copy number variants of this locus are associated with a high risk for neuropsychiatric diseases including autism spectrum disorder and schizophrenia. Studies in zebrafish point to a role of KCTD13 in proliferation of neural precursor cells which may contribute to macrocephaly in 16p11.2 deletion carriers. KCTD13 is highly expressed in the fetal human brain and in mouse cortical neurons, but its contribution to the development and function of mammalian neurons is not completely understood. In the present study, we deleted the KCTD13 gene in human-induced pluripotent stem cells (iPSCs) using CRISPR/Cas9 nickase. Following neural differentiation of KCTD13 deficient and isogenic control iPSC lines, we detected a moderate but significant inhibition of DNA synthesis and proliferation in KCTD13 deficient human neural precursor cells. KCTD13 deficient cortical neurons derived from iPSCs showed decreased neurite formation and reduced spontaneous network activity. RNA-sequencing and pathway analysis pointed to a role for ERBB signaling in these phenotypic changes. Consistently, activating and inhibiting ERBB kinases rescued and aggravated, respectively, impaired neurite formation. In contrast to findings in non-neuronal human HeLa cells, we did not detect an accumulation of the putative KCTD13/Cullin-3 substrate RhoA, and treatment with inhibitors of RhoA signaling did not rescue decreased neurite formation in human KCTD13 knockout neurons. Taken together, our data provide insight into the role of KCTD13 in neurodevelopmental disorders, and point to ERBB signaling as a potential target for neuropsychiatric disorders associated with KCTD13 deficiency.

中文翻译：

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CRISPR / Cas9介导的神经精神病风险基因KCTD13的敲除导致诱导的多能干细胞衍生的人类皮层神经元发育缺陷。

人KCTD13基因位于16p11.2位点内，该位点的拷贝数变异与神经精神疾病（包括自闭症谱系障碍和精神分裂症）的高风险相关。在斑马鱼中的研究指出，KCTD13在神经前体细胞增殖中的作用，这可能会导致16p11.2缺失携带者的大头畸形。KCTD13在胎儿的人脑和小鼠皮质神经元中高度表达，但其对哺乳动物神经元的发育和功能的贡献尚不完全清楚。在本研究中，我们使用CRISPR / Cas9切口酶删除了人类诱导的多能干细胞（iPSC）中的KCTD13基因。在对KCTD13缺陷和等基因控制iPSC品系进行神经分化后，我们在KCTD13缺陷型人类神经前体细胞中检测到对DNA合成和增殖的中等但显着的抑制作用。源自iPSC的KCTD13缺陷皮质神经元显示出减少的神经突形成和减少的自发网络活动。RNA测序和途径分析指出ERBB信号在这些表型变化中的作用。一致地，活化和抑制的ERBB激酶分别被拯救和加剧，损害了神经突的形成。与在非神经元人类HeLa细胞中发现的结果相反，我们没有检测到假定的KCTD13 / Cullin-3底物RhoA的积聚，并且用RhoA信号抑制剂处理不能挽救人类KCTD13基因敲除神经元中神经突的减少。综上所述，我们的数据可深入了解KCTD13在神经发育障碍中的作用，