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Dissertation/Thesis Abstract

Endocytosis-Associated Guanine Nucleotide Exchange Factor Rabgef1 Facilitates the Biogenesis of Outer Segments in Mammalian Photoreceptors
by Hargrove, Passley, Ph.D., The George Washington University, 2018, 129; 10690275
Abstract (Summary)

Rod and cone photoreceptors in the retina are polarized sensory neurons that possess uniquely modified primary cilium, called the outer segment, to capture photons. Circadian-mediated shedding and renewal of outer segment membrane discs requires extensive vesicular transport of protein cargo from the endoplasmic reticulum and Golgi to the base of the cilium. Endocytosis is vesicle transport process of capturing and/or recycling extrinsic components and is shown to occur in retina of early vertebrates, such as Xenopus laevis. In this thesis, I have explored the hypothesis that a critical endocytosis-associated protein Rabgef1 is critical for the genesis of photoreceptor outer segments in the mammalian retina. After demonstrating high expression of Rabgef1 concordant with photoreceptor maturation, I characterized morphology and function of retina from Rabgef1-loss of function (Rabgef1–/–) mice. Though no gross defect was observed by histology and immunohistochemistry before eye opening (postnatal day 14), transmission electron microscopy demonstrated ultrastructural defects in photoreceptor outer segments by P8. Progressive, yet rapid, photoreceptor degeneration and near-complete ablation of the visual response were evident at and after P15. I show that the outer segment defect noted in Rabgef1–/– mice was not due to defective ciliogenesis or trafficking of cargo proteins to the cilium. In concordance with other systems, Rabgef1 was enriched in purified endocytic vesicles from the retina and interacted with Rabaptin5, confirming its role in Rab5-mediated endocytosis. Curiously, Rabgef1–/– photoreceptors accumulated enlarged vesicular/endosomal structures within the inner segment, similar to loss of function mutations in the yeast orthologue of Rabgef1, Vps9p. My studies provide the first evidence of an essential role of Rabgef1-mediated fusion and recycling of endocytic vesicles in the formation and/or renewal of outer segment membrane discs in the mammalian retina. Rabgef1 and other components of the endocytic pathway should therefore be considered as candidates for human retinopathies.

Indexing (document details)
Advisor: Swaroop, Anand, Moody, Sally
Commitee: Corbin, Joshua, Lee, Chi-Hon
School: The George Washington University
Department: Molecular Medicine
School Location: United States -- District of Columbia
Source: DAI-B 79/05(E), Dissertation Abstracts International
Subjects: Biology, Molecular biology, Neurosciences
Keywords: Endocytosis, Outer segment, Photoreceptor, Rabgef1
Publication Number: 10690275
ISBN: 978-0-355-59809-4
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