Author ORCID Identifier
Semester
Fall
Date of Graduation
2024
Document Type
Dissertation (Campus Access)
Degree Type
PhD
College
School of Medicine
Department
Biochemistry
Committee Chair
Visvanathan Ramamurthy
Committee Member
Michael Schaller
Committee Member
Peter Mathers
Committee Member
Wen-Tao Deng
Committee Member
Maxim Sokolov
Committee Member
Gordon Meares
Abstract
Prominin 1 (PROM1) is a pentaspan transmembrane glycoprotein localized on the nascent photoreceptor discs. Mutations in PROM1 are linked to various retinal diseases. In this study, we showed that PROM1 depletion causes visual impairment in mice as early as post-natal day 12 (P12). By P30, these animals had irreversible retinal degeneration, evident in photoreceptor cell death. Additionally, PROM1 depletion causes severely malformed outer segments as early as P12 without apparent cell death, indicating the role of PROM1 in outer segment development and maintenance.
Actin network-driven membrane evagination at the base of the outer segment is an indispensable process for forming new discs and maintaining outer segment homeostasis. Structural similarities between the photoreceptor outer segments of actin-network disrupted micePROM1 knock-out mice indicate that PROM1 might also be involved in the photoreceptor outer segments morphogenesis. Thus, we aimed to assess the role of PROM1 C-terminus tail in retinal disorders and photoreceptor development by using murine models. We generated three novel mouse models via CRISPR/Cas9 technology where the C-terminus of endogenous PROM1 is truncated at various lengths (PROM1-Δ42 and PROM1-Δ44) or mutated at a single amino acid level (PROM1-D825N). Electroretinogram analysis showed that all three PROM1-ΔC mouse models have reduced rod and cone function compared to wild-type littermate controls. Surprisingly, PROM1-Δ44 mice had reduced photoreceptor function even with a single copy of mutant PROM1. Our preliminary ultrastructural imaging via transmission electron microscopy revealed that the photoreceptor outer segments of PROM1-Δ42 and PROM1-D825N mice are severely malformed. However, the degree of outer segment defects and overall outer segment disc organization were not identical.
Together, our results highlight the intricate role of the C-terminal tail of PROM1 in photoreceptor function, disc formation, and outer segment morphogenesis. We hypothesize that PROM1 is an essential component of a protein network that orchestrates together to form and maintain photoreceptor outer segments. This study will further aid us in deciphering the mechanism behind PROM1-mediated inherited blindness.
Recommended Citation
Yanardag, Sila, "Prominin-1 (PROM1) is Needed for the Photoreceptor Outer Segment Development and Vision" (2024). Graduate Theses, Dissertations, and Problem Reports. 12896.
https://researchrepository.wvu.edu/etd/12896