Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder

Molecular Psychiatry
A K TilotC Eng

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor Pten are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the Pten protein, and we developed the Pten(m3m4) model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by 6 weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA sequencing, we found progressive disruption of neural gene expression in Pten(m3m4) mice from 2-6 weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly coexpressed human ASD-susceptibility genes. Co...Continue Reading

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Citations

Apr 30, 2017·The European Journal of Neuroscience·Yuri BozziSimona Casarosa
Jun 13, 2018·Human Molecular Genetics·Lamis YehiaCharis Eng
Jul 17, 2019·Cold Spring Harbor Perspectives in Medicine·Thomas W Frazier
Oct 2, 2019·Cold Spring Harbor Perspectives in Medicine·Joanne Ngeow, Charis Eng
Dec 3, 2016·Frontiers in Cellular Neuroscience·Yu-Chih LinGene J Blatt
Jan 8, 2019·The Journal of Clinical Investigation·Lamis YehiaCharis Eng
Aug 12, 2017·Frontiers in Cellular Neuroscience·Franz OswaldHolger Herlyn
Feb 20, 2019·Diseases·Satoru MatsudaYasuko Kitagishi
Oct 9, 2019·Translational Psychiatry·Robyn M BuschUNKNOWN Developmental Synaptopathies Consortium
Jan 12, 2021·EMBO Molecular Medicine·Mihyun BaeEunjoon Kim
Sep 10, 2020·Progress in Neurobiology·Ning AnBart P F Rutten
May 20, 2021·Nature Communications·Felix D WeissMatthias Merkenschlager

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Datasets Mentioned

BETA
GSE59318

Methods Mentioned

BETA
RNA-seq
RNAseq

Software Mentioned

Cufflinks
BiNGO
R package
Ingenuity Pathway Analysis
R
cummeRbund
Cytoscape
BioMart
Brainspan
Tophat

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