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Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

Reut Suliman, Ben Title, Yahel Cohen, Maayan Tal, Nitzan Tal, Bjorg Gudmundsdottir, Kristbjorn O. Gudmundsson, Jonathan R Keller, Guo-Jen Huang, Yosef Yarom, Sagiv Shifman
doi: https://doi.org/10.1101/437442
Reut Suliman
1Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Ben Title
2Department of Neurobiology, The Institute of Life Sciences and Edmond & Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem, Israel
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Yahel Cohen
1Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Maayan Tal
1Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Nitzan Tal
1Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Bjorg Gudmundsdottir
3Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
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Kristbjorn O. Gudmundsson
3Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
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Jonathan R Keller
3Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
4Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Bldg. 560/32-31D, 1050 Boyles Street, Frederick, MD 21702, USA
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Guo-Jen Huang
5Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Yosef Yarom
2Department of Neurobiology, The Institute of Life Sciences and Edmond & Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem, Israel
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  • For correspondence: yosef.rarom@mail.huji.ac.il
Sagiv Shifman
1Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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  • For correspondence: sagiv.shifman@mail.huji.ac.il
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Abstract

Genes implicated in autism spectrum disorder (ASD) are enriched with chromatin regulators, but the mechanisms leading to the abnormal behavior and cognition are still unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior. We generated conditional knockout mice with brain-specific mutation in Pogz, a heterochromatin regulator recurrently mutated in ASD and other neurodevelopmental disorders, and demonstrated that these mice display phenotypes that resemble the human condition. Pogz deficiency led to smaller brain, growth impairment, motor learning deficits, and increased social interactions that mimic the human overly friendly phenotype. At the molecular level, reporter assay indicated that POGZ functions as a negative regulator of transcription through its interaction with HP1 proteins. In accordance, we found a significant upregulation of gene expression, most notably in the cerebellum. Furthermore, Pogz deficiency was associated with a significant reduction in the firing frequency of simple and complex spikes in cerebellar Purkinje cells with no changes in their intrinsic properties. Overall, our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and to motor and social abnormalities in ASD.

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Posted October 08, 2018.
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Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology
Reut Suliman, Ben Title, Yahel Cohen, Maayan Tal, Nitzan Tal, Bjorg Gudmundsdottir, Kristbjorn O. Gudmundsson, Jonathan R Keller, Guo-Jen Huang, Yosef Yarom, Sagiv Shifman
bioRxiv 437442; doi: https://doi.org/10.1101/437442
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Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology
Reut Suliman, Ben Title, Yahel Cohen, Maayan Tal, Nitzan Tal, Bjorg Gudmundsdottir, Kristbjorn O. Gudmundsson, Jonathan R Keller, Guo-Jen Huang, Yosef Yarom, Sagiv Shifman
bioRxiv 437442; doi: https://doi.org/10.1101/437442

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