对携带 NRXN1-α 双等位基因突变的自闭症患者进行单细胞分析，揭示了神经祖细胞中命运选择的偏倚和神经元功能的损伤。
Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality.
机构信息
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
出版信息
Exp Cell Res. 2019 Oct 1;383(1):111469. doi: 10.1016/j.yexcr.2019.06.014. Epub 2019 Jul 12.
We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
我们从健康对照个体和一名携带 NRXN1-α 双等位基因缺失的自闭症谱系障碍个体中生成了人类诱导多能干细胞和分化细胞。我们研究了 NRXN1-α 在神经诱导和神经分化过程中的表达情况，观察到 NRXN1-α 在早期神经诱导和神经元分化过程中起着关键作用。单细胞 RNA-seq 鉴定出携带 NRXN1-α 缺失的神经干细胞向放射状胶质样细胞身份转变，并揭示了分化星形胶质细胞的比例更高。此外，单细胞 RNA-seq 分析鉴定出携带 NRXN1-α 缺失的神经元细胞不成熟，表现出钙信号活性显著降低，并在电生理学研究中表现出受损的成熟动作电位特征。我们的观察结果表明，NRXN1-α 在神经干细胞的有效建立、神经元分化以及功能性兴奋性神经元细胞的成熟过程中发挥着重要作用。
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