The histone methyltransferase SETD2 regulates adult brain structure, connectivity and neurogenesis

Epigenetic mechanisms are crucial for neocortical development. Recent work has highlighted that ablation of Setd2, which encodes a SET domain lysine methyltransferase, from the mouse dorsal telencephalon results in deficits in reciprocal cortico-thalamic connectivity. However, analysis of broader cortical phenotypes in this model has yet to be performed. Here, we addressed this, revealing that dorsal telencephalon-specific ablation of Setd2 results in decreased structural volumes across the entire adult brain, particularly within the hippocampus. Moreover, while homozygous Setd2-deficient brains exhibited apparently normal axonal integrity within the corpus callosum, axonal connections arising from the hippocampus were significantly impacted. Furthermore, whole brain structural connectivity was significantly altered in the absence of Setd2. Finally, we revealed structural, morphological and cellular changes within the hippocampal dentate gyrus of mutant mice. Collectively, these findings demonstrate a key role for SETD2 function in the development of the adult brain.