April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Deletion of Focal Adhesion Kinase From the Retinal Pigment Epithelium Results in Progressive Retinal Degeneration in Mice
Author Affiliations & Notes
  • B. T. Pawlikowski
    Ophthalmology, University of California San Francisco, San Francisco, California
  • C. Bouquet
    Ophthalmology, University of California San Francisco, San Francisco, California
  • H. Yang
    Ophthalmology, University of California San Francisco, San Francisco, California
  • G. Nielsen
    Ophthalmology, University of California San Francisco, San Francisco, California
  • D. Yasumura
    Ophthalmology, University of California San Francisco, San Francisco, California
  • M. Matthes
    Ophthalmology, University of California San Francisco, San Francisco, California
  • J. L. Duncan
    Ophthalmology, University of California San Francisco, San Francisco, California
  • P. Chambon
    Génétique et Physiologie de Signalisation Nucléaire, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France
  • M. M. LaVail
    Ophthalmology, University of California San Francisco, San Francisco, California
  • H. Beggs
    Ophthalmology, University of California San Francisco, San Francisco, California
  • Footnotes
    Commercial Relationships  B.T. Pawlikowski, None; C. Bouquet, None; H. Yang, None; G. Nielsen, None; D. Yasumura, None; M. Matthes, None; J.L. Duncan, None; P. Chambon, None; M.M. LaVail, None; H. Beggs, None.
  • Footnotes
    Support  NIH grants EY017379, EY002162, EY01919. HB is a recipient of the RPB Career Development Award.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 5203. doi:
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      B. T. Pawlikowski, C. Bouquet, H. Yang, G. Nielsen, D. Yasumura, M. Matthes, J. L. Duncan, P. Chambon, M. M. LaVail, H. Beggs; Deletion of Focal Adhesion Kinase From the Retinal Pigment Epithelium Results in Progressive Retinal Degeneration in Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5203.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Disruption of the retinal pigment epithelium (RPE) is a key factor and early event in many forms of retinal degeneration. In order to gain insight into RPE cellular function and understand how RPE-specific defects lead to pathological changes in the retina, we have specifically deleted focal adhesion kinase (FAK) from the RPE. FAK, a cytoplasmic kinase expressed by RPE cells, is a critical signaling node that is activated following engagement of adhesion and growth factor receptors. However, the scope of its function in RPE cells remains unknown.

Methods: : To conditionally delete FAK from the RPE, mice carrying a floxed FAK allele were crossed to mice expressing Cre recombinase under control of an RPE-specific promoter (tyrosinase-related protein1). Embryonic and adult eyes from control, heterozygote and homozygote mutant mice were then analyzed using a variety of assays.

Results: : Conditional deletion of FAK from the RPE causes a severe progressive retinal degeneration starting at approximately 1 month of age that was accompanied by a loss of visual function as measured by ERG. FAK-mutant RPE cells display size and shape changes, alterations to apical-basal specializations, compromised tight junctions and a dramatic 5-fold reduction in cell number. Reduced cell numbers are not due to apoptosis but can be accounted for by an early cell cycle exit at E15.5. Furthermore, phagocytosis is disrupted in vivo as shown by decreased Mertk activation and impaired phagosome formation. Heterozygote mice missing a single copy of FAK show the same decrease in RPE cell number, indicating that RPE cells are uniquely sensitive to changes in FAK dosage. Interestingly, heterozygote mice exhibit only a minor retinal degeneration indicating that decreased RPE cell number is not sufficient to account for the severity of defects observed in homozygous FAK-/- RPE mice.

Conclusions: : This study demonstrates for the first time an essential in vivo role for FAK in controlling 1) RPE cell proliferation and 2) photoreceptor phagocytosis/recycling.

Keywords: retinal pigment epithelium • transgenics/knock-outs • retinal degenerations: cell biology 
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