Loss of the endoplasmic reticulum protein canopy 1 disrupts the function and circuit organization of V2R-expressing vomeronasal sensory neurons.

The vomeronasal organ (VNO) is a specialized chemosensory structure that detects chemical cues involved in predator avoidance, social interactions and reproductive behaviors. In mice, the VNO contains distinct vomeronasal sensory neurons (VSNs) that express vomeronasal receptors (VRs) and formyl peptide receptors. Apical VSNs express Meis2, V1Rs and Gαi2, whereas basal VSNs express Tfap2e (also known as AP-2ε), V2Rs and Gαo. Type 2 VRs (V2Rs) are classified into families A-E, and basal neurons co-express a family C receptor with a VR from another family. Single-cell RNA-sequencing identified ∼980 genes differentially expressed between V1R- and V2R-expressing neurons, many of which are linked to endoplasmic reticulum (ER) functions. Notably, canopy 1 (Cnpy1) is highly enriched in V2R-expressing neurons. The VNO of Cnpy1 knockout mice develops normally but undergoes progressive loss of V2R-expressing neurons, which is associated with increased ER stress gene expression, upregulation of family C V2R mRNAs and reduced V2R protein levels. V2R-expressing VSNs in Cnpy1 knockouts fail to respond to pheromones, show altered guidance and adhesion gene expression, and display disrupted connectivity with the accessory olfactory bulb. These findings emphasize the role of cell-specific ER protein repertoires in maintaining neuronal function.