Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration

Autoři: Passley Hargrove-Grimes aff001;  Anupam K. Mondal aff001;  Jessica Gumerson aff001;  Jacob Nellissery aff001;  Angel M. Aponte aff003;  Linn Gieser aff001;  Haohua Qian aff004;  Robert N. Fariss aff005;  Juan S. Bonifacino aff006;  Tiansen Li aff001;  Anand Swaroop aff001
Působiště autorů: Neurobiology, Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff001;  Institute of Biomedical Sciences, George Washington University, Washington, District of Columbia, United States of America aff002;  Proteomics Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff003;  Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff004;  Biological Imaging Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff005;  Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute for Child Health and Development, National Institutes of Health, Bethesda, Maryland, United States of America aff006
Vyšlo v časopise: Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration. PLoS Genet 16(12): e1009259. doi:10.1371/journal.pgen.1009259
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009259


Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype.

Klíčová slova:

Autophagic cell death – Endocytosis – Eyes – Immunostaining – Photoreceptors – Phototransduction – Retina – Vision


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