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Author (up) Zeng, L.; Zhang, P.; Shi, L.; Yamamoto, V.; Lu, W.; Wang, K. url  doi
  Title Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models Type Journal Article
  Year 2013 Publication PloS one Abbreviated Journal PLoS One  
  Volume 8 Issue 3 Pages e59685  
  Keywords Astrocytes/cytology/metabolism; Cell Adhesion Molecules, Neuronal/*genetics/*metabolism; Cell Differentiation/genetics; DNA Transposable Elements; Developmental Disabilities/genetics/metabolism; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Induced Pluripotent Stem Cells/cytology/metabolism; Nerve Tissue Proteins/*genetics/*metabolism; Neural Stem Cells/cytology/metabolism; Neurons/cytology/metabolism; Protein Interaction Maps; Signal Transduction; Stem Cells/*cytology/*metabolism  
  Abstract Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) as models to investigate the functional impacts of NRXN1 knockdown. We first generated hiPSCs from skin fibroblasts and differentiated them into neural stem cells (NSCs). We reduced NRXN1 expression in NSCs via a controlled shRNAmir-based knockdown system during differentiation, and monitored the transcriptome alteration by RNA-Seq and quantitative PCR at several time points. Interestingly, half reduction of NRXN1 expression resulted in changes of expression levels for the cell adhesion pathway (20 genes, P = 2.8x10(-6)) and neuron differentiation pathway (13 genes, P = 2.1x10(-4)), implicating that single-gene perturbation can impact biological networks important for neurodevelopment. Furthermore, astrocyte marker GFAP was significantly reduced in a time dependent manner that correlated with NRXN1 reduction. This observation was reproduced in both hiPSCs and hESCs. In summary, based on in vitro models, NRXN1 deletions impact several biological processes during neurodevelopment, including synaptic adhesion and neuron differentiation. Our study highlights the utility of stem cell models in understanding the functional roles of copy number variations (CNVs) in conferring susceptibility to neurodevelopmental diseases.  
  Address Zilhka Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1932-6203 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23536886; PMCID:PMC3607566 Approved no  
  Call Number refbase @ user @ Serial 16899  
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