Abnormal neocortex arealization and Sotos-like syndrome–associated behavior in <i>Setd2</i> mutant mice

Abstract

Proper formation of area identities of the cerebral cortex is crucial for cognitive functions and social behaviors of the brain. It remains largely unknown whether epigenetic mechanisms, including histone methylation, regulate cortical arealization. Here, we removed SETD2, the methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and showed that <i>Setd2</i> is required for proper cortical arealization and the formation of cortico-thalamo-cortical circuits. Moreover, <i>Setd2</i> conditional knockout mice exhibit defects in social interaction, motor learning, and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing <i>SETD2</i> mutations. SETD2 maintains the expression of clustered protocadherin (<i>cPcdh</i>) genes in an H3K36me3 methyltransferase-dependent manner. Aberrant cortical arealization was recapitulated in <i>cPcdh</i> heterozygous mice. Together, our study emphasizes epigenetic mechanisms underlying cortical arealization and pathogenesis of the Sotos-like syndrome.