转录网络将类似突触结合蛋白3鉴定为神经发育早期皮质神经元迁移的调节因子。

Transcriptional networks identify synaptotagmin-like 3 as a regulator of cortical neuronal migration during early neurodevelopment.

作者信息

Dong Xinran, Yang Lin, Liu Kaiyi, Ji Xiaoli, Tang Chuanqing, Li Wanxing, Ma Ling, Mei Yuting, Peng Ting, Feng Ban, Wu Ziyan, Tang Qingyuan, Gao Yanyan, Yan Kai, Zhou Wenhao, Xiong Man

机构信息

Molecular Medical Center, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.

Molecular Medical Center, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China; Stem Cell Center, Children's Hospital of Fudan University, Shanghai 201102, China.

出版信息

Cell Rep. 2021 Mar 2;34(9):108802. doi: 10.1016/j.celrep.2021.108802.

DOI:10.1016/j.celrep.2021.108802

PMID:33657377

Abstract

Human brain development is a complex process involving neural proliferation, differentiation, and migration that are directed by many essential cellular factors and drivers. Here, using the NetBID2 algorithm and developing human brain RNA sequencing dataset, we identify synaptotagmin-like 3 (SYTL3) as one of the top drivers of early human brain development. Interestingly, SYTL3 exhibits high activity but low expression in both early developmental human cortex and human embryonic stem cell (hESC)-derived neurons. Knockout of SYTL3 (SYTL3-KO) in human neurons or knockdown of Sytl3 in embryonic mouse cortex markedly promotes neuronal migration. SYTL3-KO causes an abnormal distribution of deep-layer neurons in brain organoids and reduces presynaptic neurotransmitter release in hESC-derived neurons. We further demonstrate that SYTL3-KO-accelerated neuronal migration is modulated by high expression of matrix metalloproteinases. Together, based on bioinformatics and biological experiments, we identify SYTL3 as a regulator of cortical neuronal migration in human and mouse developing brains.

摘要

人类大脑发育是一个复杂的过程，涉及神经增殖、分化和迁移，这些过程由许多重要的细胞因子和驱动因素引导。在这里，我们使用NetBID2算法并开发人类大脑RNA测序数据集，将突触结合蛋白样3（SYTL3）确定为早期人类大脑发育的主要驱动因素之一。有趣的是，SYTL3在早期发育的人类皮质和人类胚胎干细胞（hESC）衍生的神经元中均表现出高活性但低表达。在人类神经元中敲除SYTL3（SYTL3-KO）或在胚胎小鼠皮质中敲低Sytl3均显著促进神经元迁移。SYTL3-KO导致脑类器官中深层神经元分布异常，并减少hESC衍生神经元中的突触前神经递质释放。我们进一步证明，SYTL3-KO加速的神经元迁移受基质金属蛋白酶高表达的调节。总之，基于生物信息学和生物学实验，我们确定SYTL3是人类和小鼠发育大脑中皮质神经元迁移的调节因子。