Semester

Fall

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Peter Mathers

Committee Member

Visvanathan Ramamurthy

Committee Member

Charles Anderson

Committee Member

Elena Pugacheva

Committee Member

Justin Legleiter

Abstract

Primary cilia are highly specialized organelles that regulate signaling, trafficking, and sensory perception across multiple tissues, including the retina. The small GTPase ADP Ribosylation Factor-Like Protein 13B (ARL13B) is an atypical ARF-family protein enriched in cilia. ARL13B acts as a guanine exchange factor (GEF) for another small GTPase ARF-like Protein 3 (ARL3). Mutations in ARL13B cause Joubert syndrome, a ciliopathy characterized by brain malformation, developmental delays, and retinal degeneration. Despite ARL13B’s known ciliary localization and clinical relevance, ARL13B’s precise functions in cilia remain poorly defined. This dissertation investigates the cilia-specific roles and GEF-specific roles of ARL13B in photoreceptors using two knock-in mouse models, the cilia-excluded ARL13B V358A and the GEF-deficient ARL13B R79Q mutants. We show that loss of ciliary ARL13B causes cone axoneme shortening, mislocalization of intraflagellar transport (IFT) proteins, and accumulation of phosphoinositide-binding proteins, such as TULP1, in cone outer segments. These structural and molecular defects lead to early cone degeneration followed by rod degeneration, demonstrating that ARL13B’s ciliary localization is critical for photoreceptor maintenance and visual function. Additionally, we show that this phenotype is distinctly different than when ARL13B has impaired GEF functioning. Altogether these findings show the unique vulnerability of cone photoreceptors to axoneme disruption and further our understanding of cilia biology.

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