Arap1 deficiency causes photoreceptor degeneration in mice

Ala Moshiri, Devin Humpal, Brian C Leonard, Denise Imai, Addy Tham, Lynette Bower, Dave Clary, Thomas M Glaser, Kevin C K Lloyd, Christopher J Murphy

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Methods. 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. Results. 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. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)1709-1718
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number3
DOIs
StatePublished - Mar 1 2017

Fingerprint

Retina
Guanosine
Knockout Mice
Neuroglia
Eye Abnormalities
ADP-Ribosylation Factors
Pallor
GTPase-Activating Proteins
Electroretinography
Retinal Degeneration
Retinitis Pigmentosa
Survival
Photography
Endosomes
Optical Coherence Tomography
National Institutes of Health (U.S.)
Protein Transport
Optic Nerve
Epidermal Growth Factor Receptor
Blood Vessels

Keywords

  • Photoreceptors
  • Retinitis pigmentosa
  • Rod-cone degeneration

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Arap1 deficiency causes photoreceptor degeneration in mice. / Moshiri, Ala; Humpal, Devin; Leonard, Brian C; Imai, Denise; Tham, Addy; Bower, Lynette; Clary, Dave; Glaser, Thomas M; Lloyd, Kevin C K; Murphy, Christopher J.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 3, 01.03.2017, p. 1709-1718.

Research output: Contribution to journalArticle

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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 is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Methods. 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. Results. 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 M{\"u}ller glia, and not in photoreceptors, implicating a role for M{\"u}ller glia in photoreceptor survival. Conclusions. 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.",
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AU - Humpal, Devin

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AU - Imai, Denise

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AU - Bower, Lynette

AU - Clary, Dave

AU - Glaser, Thomas M

AU - Lloyd, Kevin C K

AU - Murphy, Christopher J

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