ORCID
https://orcid.org/0000-0001-8655-5469
Date of Award
Summer 2026
Language
English
Embargo Period
8-1-2027
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Biological Sciences
Program
Biology
First Advisor
Paolo Forni
Committee Members
Melinda Larsen, Morgan Sammons, Jean-Pierre Saint-Jeannet
Keywords
GPCR, VNO, Vomeronasal, Proteostasis, Cnpy1, Neurodegeneration
Subject Categories
Other Cell and Developmental Biology
Abstract
The vomeronasal organ (VNO) is a specialized chemosensory organ responsible for detecting the chemical cues that regulate predator avoidance, social recognition, and reproductive behavior in many vertebrates. In rodents, the VNO is populated by two major classes of vomeronasal sensory neurons (VSNs) that arise from a common progenitor pool yet adopt profoundly divergent molecular identities: apical VSNs express monoallelic class-A V1Rs coupled to Gαi2 and project to the anterior accessory olfactory bulb (AOB), whereas basal VSNs express combinatorial repertoires of class-C V2Rs coupled to Gαo and project to the posterior AOB. Neuronal identity has traditionally been understood as the product of transcription factors and the gene regulatory networks they command. Transcription alone, however, cannot account for function: every functional protein begins as a transcript that must ultimately be translated into a correctly folded, assembled, and trafficked protein. Notably, components of the endoplasmic reticulum (ER) and proteostasis machinery are among the largest classes of genes differentially expressed between V1R and V2R VSNs. This dissertation advances the argument that neuronal identity extends beyond the transcriptome to encompass a cell-type-specific ER, and that the evolution of increasingly complex receptor repertoires must be accompanied by specialization of the intracellular machinery required to produce them.
Single-cell transcriptomic analysis identified approximately 980 genes differentially expressed between apical and basal VSNs, a disproportionate fraction of which encode ER-resident chaperones and quality-control factors, including the ER chaperone GRP78/HSPA5 (BiP), Calreticulin-4 (Calr4), and Canopy1 (Cnpy1), the founding member of the saposin-fold Canopy family and one of the most highly enriched transcripts in V2R-expressing neurons. To test whether a single ER component is required for the identity and function of a defined neuronal population, the consequences of Cnpy1 loss of function in vivo were characterized. The VNO of Cnpy1 knockout mice develops normally but undergoes progressive, selective loss of V2R VSNs, accompanied by elevated ER-stress gene expression, paradoxical upregulation of family-C V2R mRNAs, reduced V2R protein at the sensory microvilli, a failure to respond to pheromonal stimulation, and disrupted axonal connectivity with the AOB. These findings establish Cnpy1 as an essential, cell-type-restricted node in the gene regulatory and proteostatic network that sustains basal VSNs and indicate that individual V2R families differ in their dependence on specific ER machinery.
Together, this work reframes the ER not as a uniform housekeeping compartment but as a molecularly specialized organelle tuned to the proteomic demands of each neuronal type. It argues that receptor repertoires and the proteostasis programs that support them co-evolve, likely under the coordinated control of terminal-selector transcription factors such as AP-2ε, which regulates both V2R expression and the ER components required for V2R maturation. By demonstrating that the loss of a single ER protein can selectively dismantle the identity of one neuronal population while sparing its neighbor, this dissertation supports a broader principle: that each neuronal type may require its own dedicated proteostasis program, and that the specialization of intracellular protein-processing machinery is an integral, and evolutionarily coupled, dimension of neuronal diversity.
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Mathias, Nicholas A., "Canopy1 Highlights the Significance of ER Protein Repertoires in the Proper Proteostasis and Function of Neurons Expressing Evolutionarily Divergent GPCRs" (2026). Electronic Theses & Dissertations (2024 - present). 540.
https://scholarsarchive.library.albany.edu/etd/540