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

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.

Phenotypic expansion of POGZ‐related intellectual disability syndrome (White‐Sutton syndrome)

“…Neurocognitive/behavioral features are universal but are highly variable from low‐normal intellect to severe intellectual disability. Learning and behavioral abnormalities are also observed in Drosophila and mouse models (Stessman et al, ; Suliman et al, ).…”

Value-complexity tradeoff explains mouse navigational learning

“…The generation of the Pogz +/− mice with deletion of exons 13-19 has been described previously [38]. Heterozygous loss-offunction mutations in the human POGZ gene are associated with intellectual disability and autism spectrum disorder independent of gender [39]. The heterozygous progeny was generated by crossing heterozygous mice with wildtype mice.…”