Arap1 Deficiency Causes Photoreceptor Degeneration in Mice.
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 is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina.



Genetically engineered Arap1 knockout mice were screened for ocular abnormalities in the National Institutes of Health Knockout Mouse Production and Phenotyping (KOMP2) Project. Arap1 knockout and wild-type eyes were imaged using optical coherence tomography and fundus photography, and analyzed by immunohistochemistry.



Arap1-/- mice develop a normal appearing retina, but undergo photoreceptor degeneration starting at 4 weeks postnatal age. The fundus appearance of mutants is notable for pigmentary changes, optic nerve pallor, vascular attenuation, and outer retinal thinning, reminiscent of retinitis pigmentosa in humans. Immunohistochemical studies suggest the cell death is predominantly in the outer nuclear layer. Functional evaluation of the retina by electroretinography reveals amplitudes are reduced. Arap1 is detected most notably in Müller glia, and not in photoreceptors, implicating a role for Müller glia in photoreceptor survival.



Arap1 is necessary for normal photoreceptor survival in mice, and may be a novel gene relevant to human retinal degenerative processes, although its mechanism is unknown. Further studies in this mouse model of retinal degeneration will give insights into the cellular functions and signaling pathways in which Arap1 participates.
Department of Ophthalmology and Vision Science, School of Medicine, U.C. Davis, Sacramento, California, United States.
Ala
A
Moshiri
Department of Ophthalmology and Vision Science, School of Medicine, U.C. Davis, Sacramento, California, United States.
Devin
D
Humpal
Department of Veterinary Surgical and Radiological Sciences, School of Veterinary Medicine, U.C. Davis, Davis, California, United States.
Brian C
BC
Leonard
Comparative Pathology Laboratory, U.C. Davis, Davis, California, United States.
Denise M
DM
Imai
Department of Ophthalmology and Vision Science, School of Medicine, U.C. Davis, Sacramento, California, United States.
Addy
A
Tham
Mouse Biology Program, U.C. Davis, Davis, California, United States.
Lynette
L
Bower
Mouse Biology Program, U.C. Davis, Davis, California, United States.
Dave
D
Clary
Department of Cell Biology and Human Anatomy, U.C. Davis, Davis, California, United States.
Thomas M
TM
Glaser
Mouse Biology Program, U.C. Davis, Davis, California, United States.
K C Kent
KC
Lloyd
Department of Ophthalmology and Vision Science, School of Medicine, U.C. Davis, Sacramento, California, United States 2Department of Veterinary Surgical and Radiological Sciences, School of Veterinary Medicine, U.C. Davis, Davis, California, United States.
Christopher J
CJ
Murphy
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009887:Ophthalmoscopy; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D041623:Tomography, Optical Coherence
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D004247:DNA