Transcript architecture controls oxytocin receptor abundance and physiological plasticity [transgenic_oxtr_analysis]

Using a combination of longread and shortread transcriptomics, we uncover Oxtr isoform switching as a novel mechanism of receptor regulation. Interplay of alternative transcription start sites, alternative polyadenylation and upstream open reading frames results in a substantial uncoupling of Oxtr mRNA and protein levels in mice.

We provide a mass-spectrometry-based quantitative framework for measuring endogenous OXTR protein in tissues where antibody-based measurements have been unreliable. Finally, we demonstrate that commonly used Oxtr reporter alleles modify transcript isoforms and dramatically alter endogenous OXTR protein abundance. Collectively, this work provides a quantitative molecular framework for measuring and interpreting endogenous OXTR expression and demonstrates that physiological regulation of OXTR abundance is achieved by transcriptional regulation and coordinated switching between transcript isoforms that differ in post-transcriptional regulation and translation.