TIFR researchers identify protein essential for survival and function of vomeronasal sensory neurons

Researchers at the Tata Institute of Fundamental Research (TIFR), Hyderabad, have identified a mammalian protein, Cnpy1 (Canopy1), that is essential for the survival and function of vomeronasal sensory neurons in mice. Published in the journal Proceedings of the National Academy of Sciences (PNAS), the study shows that Cnpy1 acts as a specialized endoplasmic‑reticulum‑associated factor required to maintain functional receptor complexes in these neurons, allowing them to thrive in an unusually high ER‑stress‑like environment.

The work focuses on the vomeronasal organ (VNO), a specialized sensory structure located in the nasal cavity of many vertebrate animals. It detects pheromones, which are chemical signals that influence behaviors such as mating, aggression, and predator avoidance. Neurons in the VNO rely on specialized receptors to detect these cues and transmit signals to the brain. Unlike most neurons, VNO neurons continuously regenerate and exhibit unusual cellular features. 

Previous work by the research team showed that a subset of these neurons develops an elaborate and expanded endoplasmic reticulum (ER), the cellular compartment responsible for protein folding and quality control. This ER is enriched with unusually high levels of proteins called chaperones that assist in folding newly synthesized proteins.

In most cell types such an ER configuration would be associated with pathological ER stress, caused by an accumulation of misfolded proteins, ultimately leading to cell death. In these neurons, however, the expanded ER enriched with chaperones appears to be a normal feature of their physiology, suggesting that they require specialized ER‑associated factors to maintain protein homeostasis and long‑term survival. 

In the current study, GVS Devakinandan, Adish Dani, and colleagues identify Cnpy1 as one such protein factor that is selectively present in the ER of VNO neurons, where it associates with pheromone receptors. Although first described in zebrafish, Cnpy1 was long thought to be non-functional in mammals. The new study identifies a previously unrecognized region of the gene, demonstrating that a full-length, functional protein is present in mice.

The group then generated mice that lack Cnpy1. Such Cnpy1-deficient mice showed reduced activation of VNO neurons by predator and opposite-sex stimuli, along with a marked deficit in male territorial aggression behavior. The researchers found that while these VNO neurons develop normally before birth, they undergo accelerated degeneration after birth in the absence of Cnpy1. Surprisingly, sensory receptors still reached the cell surface without Cnpy1, indicating that the protein is not required for receptor transport. Instead, the findings suggest that Cnpy1 plays a critical role in maintaining receptor functionality or stability within a demanding cellular environment. 

Collectively, their findings highlight an unusual adaptation in sensory neurons, where an elevated ER-stress-like state may be co-opted as part of normal cellular function rather than avoided, with factors such as Cnpy1 enabling such adaptation.

The study may also have broader implications. Similar stress-response pathways are often activated in cancer cells, which survive despite conditions that would typically trigger cell death. Understanding how VNO neurons manage such stress could provide insights into these processes in other biological contexts.