Rtel1 in hypothalamic oxytocin neurons regulates oxytocin output and social behaviors in mice

Abstract

RTEL1, a DNA helicase that resolves G-quadruplexes to maintain telomere and genome stability, has emerged as a candidate autism spectrum disorder risk gene, but its neural functions remain unknown. Here, we show that Rtel1 haploinsufficiency in mice impairs social novelty and increases marble burying and anxiety-related behaviors without affecting locomotion or spatial learning. RTEL1 is expressed in oxytocin (OXT) neurons of the hypothalamic paraventricular nucleus, where Rtel1 haploinsufficiency reduces OXT abundance and blunts social-evoked OXT sensor responses. RTEL1 associates with a G-quadruplex-forming sequence near the Oxt transcription start site, and purified RTEL1 binds and unwinds this structure in an ATP-dependent manner. Rtel1 reduction in Oxt-lineage cells recapitulates the social and OXT phenotypes, whereas adult RTEL1 re-expression in paraventricular OXT neurons increases OXT abundance and ameliorates behavioral abnormalities. These findings uncover a non-telomeric function for RTEL1 linking promoter DNA structure to hypothalamic oxytocin output and social behavior.