Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice.

Nature Communications
Reut Suliman-LavieSagiv Shifman

Abstract

Several genes implicated in autism spectrum disorder (ASD) are chromatin regulators, including POGZ. The cellular and molecular mechanisms leading to ASD impaired social and cognitive behavior are unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior as well as unveiling the underlying mechanisms. Here, we generate a brain specific conditional knockout mouse model deficient for Pogz, an ASD risk gene. We demonstrate that Pogz deficient mice show microcephaly, growth impairment, increased sociability, learning and motor deficits, mimicking several of the human symptoms. At the molecular level, luciferase reporter assay indicates that POGZ is a negative regulator of transcription. In accordance, in Pogz deficient mice we find a significant upregulation of gene expression, most notably in the cerebellum. Gene set enrichment analysis revealed that the transcriptional changes encompass genes and pathways disrupted in ASD, including neurogenesis and synaptic processes, underlying the observed behavioral phenotype in mice. Physiologically, Pogz deficiency is associated with a reduction in the firing frequency of simple and complex spikes and an increase in amplitude of the inhibitory s...Continue Reading

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Datasets Mentioned

BETA
AB10554

Methods Mentioned

BETA
transgenic
RNA-seq
PCR
genotyping
transfection
pulldown
infrared microscopy

Software Mentioned

R
LabView
Robustbase Package
edgeR
Noldus Ethovision XT11
GSEA
custom
STAR aligner
fgsea Package
EthoVision

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