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

Reut Suliman-Lavie, Ben Title, Yahel Cohen, Nanako Hamada, Maayan Tal, Nitzan Tal, Galya Monderer-Rothkoff, Bjorg Gudmundsdottir, Kristbjorn O. Gudmundsson, Jonathan R. Keller, Guo-Jen Huang, Koh-ichi Nagata, Yosef Yarom () and Sagiv Shifman ()
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Reut Suliman-Lavie: The Hebrew University of Jerusalem
Ben Title: The Hebrew University of Jerusalem
Yahel Cohen: The Hebrew University of Jerusalem
Nanako Hamada: Aichi Developmental Disability Center
Maayan Tal: The Hebrew University of Jerusalem
Nitzan Tal: The Hebrew University of Jerusalem
Galya Monderer-Rothkoff: The Hebrew University of Jerusalem
Bjorg Gudmundsdottir: National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)
Kristbjorn O. Gudmundsson: National Cancer Institute at Frederick
Jonathan R. Keller: National Cancer Institute at Frederick
Guo-Jen Huang: Chang Gung University
Koh-ichi Nagata: Aichi Developmental Disability Center
Yosef Yarom: The Hebrew University of Jerusalem
Sagiv Shifman: The Hebrew University of Jerusalem

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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 synaptic input in cerebellar Purkinje cells. Our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and behavioral abnormalities in ASD.

Date: 2020
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DOI: 10.1038/s41467-020-19577-0

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