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

Authors
  • Lam, Matti1
  • Moslem, Mohsen1
  • Bryois, Julien2
  • Pronk, Robin J1
  • Uhlin, Elias1
  • Ellström, Ivar Dehnisch3
  • Laan, Loora4
  • Olive, Jessica1
  • Morse, Rebecca1
  • Rönnholm, Harriet1
  • Louhivuori, Lauri3
  • Korol, Sergiy V5
  • Dahl, Niklas4
  • Uhlén, Per3
  • Anderlid, Britt-Marie6
  • Kele, Malin1
  • Sullivan, Patrick F2
  • Falk, Anna7
  • 1 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 3 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 4 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. , (Sweden)
  • 5 Department of Neuroscience, Uppsala University, Uppsala, Sweden. , (Sweden)
  • 6 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 7 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: [email protected] , (Sweden)
Type
Published Article
Journal
Experimental Cell Research
Publisher
Elsevier
Publication Date
Oct 01, 2019
Volume
383
Issue
1
Pages
111469–111469
Identifiers
DOI: 10.1016/j.yexcr.2019.06.014
PMID: 31302032
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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