GSE138672
Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration
Rab and associated effector proteins are involved in all steps of cargo transport through subcellular compartments during the endocytic pathway that participates in multiple cellular processes including signal transduction, protein recycling and degradation. We identified Rabgef1 (also called Rabex-5) as the only differentially expressed Rab-associated gene that exhibits strong concordance with photoreceptor maturation by mining the retinal transcriptome data. The retinas of Rabgef1-/- mice exhibit defects in photoreceptor morphology, followed by cell death, and almost complete loss of both rod and cone photoreceptor function within 3 weeks after birth. Like other cells/tissues, Rabgef1 interacts with Rabaptin5 in the retina and its loss leads to reduced early endosomes in the photoreceptor inner segments as indicated by EEA1 immunostaining. Rabgef1-/- photoreceptors abnormally accumulate autophagosomes, and proteomic profiling of endosome-enriched fractions demonstrate significant depletion of phototransduction and mitochondrial proteins. Transcriptome analysis of developing retina before the degeneration is evident reveals energy metabolism modules and gene regulatory landscape that likely suggest the trajectory of cellular changes leading to photoreceptor degeneration. Our results directly implicate endocytic pathway in outer segment biogenesis and photoreceptor development and provide strong evidence that endocytosis defects in the retina can trigger upregulation of autophagic mechanisms. We also suggest that Rabgef1 and components of the endocytic and autophagic pathways should be considered as candidates for human retinopathies. Overall design: Retinal transcriptome of Rabgef1 WT and KO mutants were profiles at three different ages: P6, P10, P14. All samples had at least two replicates. Transcriptome landscape were compared to determine the pathway changes associated with Rabgef1 loss of function.