Deficiency of Arap1 causes progressive retinal degeneration in mice

Abstract

Purpose : Small guanosine triphosphatase (GTPase) ADP-ribosylation factors (Arfs) regulate membrane traffic and actin reorganization under the control of GTPase-activating proteins (GAPs). ARAP1 is an Arf-directed GAP that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome, but the diversity of its functions are poorly understood. ARAP1 has multiple PH domains that recognize phosphatidylinositol 3,4,5-trisphosphate, can be located near both the Golgi, and/or in the plasma membrane in certain cell types, and has been shown to regulate numerous members of the Arf and Rho small GTPase protein families in vitro. Preliminary data suggests that Arap1 plays a vital role in retinal homeostasis. The aim of this study is to determine the role of Arap1 in the mammalian retina.

Methods : Genetically engineered Arap1 knockout mice were screened for ocular abnormalities. Mice were examined at 16 weeks post-natal age by indirect ophthalmoscopy. The mice were taken to necropsy and analyzed histologically by veterinary pathologists. Arap1 knockout and wild type littermate eyes were imaged at 18 weeks using optical coherence tomography and fundus photography.

Results : We found that mice deficient in ARAP1 exhibit retinal degeneration at 16 weeks post-natal age. The fundus appearance of mutants is notable for yellow drusenoid lesions and pigmentary clumping, reminiscent of human degenerative processes like age-related macular degeneration and hereditary conditions like retinitis pigmentosa. Histological findings suggest cellular death is predominantly in the outer nuclear layer of the retina, disproportionally affecting the photoreceptor layer with thinning and dysplasia.

Conclusions : Arap1 is necessary for normal photoreceptor survival in mice, and may be a novel gene relevant to human retinal degenerative processes. The mechanism of ARAP1 function in mammalian retinal development and survival is currently unknown, and is an active area of research. Further studies in this mouse model of retinal degeneration will give insights into the cellular functions and signaling pathways in which ARAP1 participates.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Pigmentary clumps and yellow drusenoid deposits are seen in the ARAP1-/- fundus (A) by 18 weeks post-natal, but not in wild type littermates (B). Optical coherence tomography of ARAP1-/- animals at this age shows profound retinal thinning in the outer retina (C) when compared with wild type animals (D).