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

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 ob...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-4827 1090-2422 1090-2422
DOI:	10.1016/j.yexcr.2019.06.014