Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality

• Published in: Experimental cell research Vol. 383; no. 1; p. 111469
• Main Authors: Lam, Matti, Moslem, Mohsen, Bryois, Julien, Pronk, Robin J., Uhlin, Elias, Ellström, Ivar Dehnisch, Laan, Loora, Olive, Jessica, Morse, Rebecca, Rönnholm, Harriet, Louhivuori, Lauri, Korol, Sergiy V., Dahl, Niklas, Uhlén, Per, Anderlid, Britt-Marie, Kele, Malin, Sullivan, Patrick F., Falk, Anna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Autism spectrum disorder; Disease modeling; Induced pluripotent stem cell; Medicin och hälsovetenskap; Neural development; Neural stem cell; Neurexin; Neurexin-1 alpha; Single cell RNA sequencing; Neurexin; Disease modeling; Neural stem cell; Induced pluripotent stem cell; Neurexin-1 alpha; Autism spectrum disorder; Single cell RNA sequencing; Neural development
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2019.06.014

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. [Display omitted] •Disease modeling of autism in iPS derived neural stem cells carrying bi-allelic NRXN1-alpha deletion.•Single cell analysis accurately resolves genes and cell identities.•Deletion of NRXN1-alpha skews neural stem cells towards radial glia-like cells with preference for generating astroglia.•Deletion of NRXN1-alpha depresses calcium-signaling activity and impairs maturation in excitatory neurons.