ABSTRACT Photoreceptor cells in the retina are highly polarized and compartmentalized neurons. Most proteins localize to a specific compartment in photoreceptors, and such compartment-specific protein localization is essential for the proper function and survival of photoreceptors. Despite considerable research efforts, however, our understanding of the mechanisms by which photoreceptors achieve compartment-specific protein localization is limited. Related to this, the pathophysiology of retinal degenerations caused by the disruption of these mechanisms is also not sufficiently understood. This is partly because of the lack of easy-to-use means to monitor protein trafficking and confinement in diseased photoreceptors. To address this need, we have developed two transgenic mouse lines, iROSRePT (inducible Reporter for the Outer Segment Renewal and Protein Trafficking) and iRATProx (inducible Reporter for ABCA4 Trafficking and Proximity labeling). In the proposed studies, we will utilize these reporter lines and four disease models representing the disruption of the ciliary gate, intraflagellar transport (IFT), and exocytotic membrane fusion machinery and investigate the precise requirements of these mechanisms for the compartmentalized protein localization in photoreceptors. We anticipate that the outcome of this study will significantly advance our understanding of the mechanisms by which photoreceptor compartment homeostasis is attained and the pathophysiology of retinal degenerations linked to defective protein trafficking and confinement. This knowledge will build a foundation to develop treatments for cilia-related retinal degenerations and assess the efficacy of newly developed therapies.