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Research Article
Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival
Jonathan A. Coleman, Xianjun Zhu, Hidayat R. Djajadi, Laurie L. Molday, Richard S. Smith, Richard T. Libby, Simon W. M. John, Robert S. Molday
Journal of Cell Science 2014 127: 1138-1149; doi: 10.1242/jcs.145052
Jonathan A. Coleman
1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Xianjun Zhu
2The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
3Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609, USA
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Hidayat R. Djajadi
1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Laurie L. Molday
1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Richard S. Smith
3Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609, USA
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Richard T. Libby
3Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609, USA
4Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
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Simon W. M. John
3Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609, USA
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  • For correspondence: molday@mail.ubc.ca Simon.John@jax.org
Robert S. Molday
1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
5Department of Ophthalmology and Visual Sciences, Centre for Macular Research, University of British Columbia, Vancouver, BC, V5Z 3N9, Canada
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  • For correspondence: molday@mail.ubc.ca Simon.John@jax.org
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ABSTRACT

ATP8A2 is a P4-ATPase that is highly expressed in the retina, brain, spinal cord and testes. In the retina, ATP8A2 is localized in photoreceptors where it uses ATP to transport phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the exoplasmic to the cytoplasmic leaflet of membranes. Although mutations in ATP8A2 have been reported to cause mental retardation in humans and degeneration of spinal motor neurons in mice, the role of ATP8A2 in sensory systems has not been investigated. We have analyzed the retina and cochlea of ATP8A2-deficient mice to determine the role of ATP8A2 in visual and auditory systems. ATP8A2-deficient mice have shortened photoreceptor outer segments, a reduction in photoresponses and decreased photoreceptor viability. The ultrastructure and phagocytosis of the photoreceptor outer segment appeared normal, but the PS and PE compositions were altered and the rhodopsin content was decreased. The auditory brainstem response threshold was significantly higher and degeneration of spiral ganglion cells was apparent. Our studies indicate that ATP8A2 plays a crucial role in photoreceptor and spiral ganglion cell function and survival by maintaining phospholipid composition and contributing to vesicle trafficking.

Footnotes

  • ↵* These authors contributed equally to this work.

  • Competing interests

    The authors declare no competing interests.

  • Author contributions

    J.A.C., X.Z., H.R.D., L.L.M., R.S.S., R.T.L. carried out the experiments. J.A.C., X.Z., R.S.M. and S.W.M.J. designed the experiments. J.A.C., R.S.M. and S.W.M.J. wrote the manuscript.

  • Funding

    This work was supported by grants from the Canadian Institutes for Health Research [grant number MOP-106667 to R.S.M.]; the National Institutes of Health [grant number EY02422 to R.S.M.; EY11721 to S.W.M.J.]; Pew Charitable Trust [S.W.M.J.]; National Science Foundation of China [grant number 81271007 to X.Z.]. J.A.C. was supported by a National Sciences and Engineering Council predoctoral studentship. R.S.M. holds a Canada Research Chair in Vision and Macular Degeneration. S.W.M.J. is an Investigator of the Howard Hughes Medical Institute. Deposited in PMC for release after 6 months.

  • Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.145052/-/DC1

  • Received October 21, 2013.
  • Accepted December 6, 2013.
  • © 2014. Published by The Company of Biologists Ltd
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Keywords

  • ATP8A2
  • Phospholipid flippase
  • P4-ATPase
  • Photoreceptors
  • Visual system
  • Spiral ganglion cells
  • Auditory system

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Research Article
Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival
Jonathan A. Coleman, Xianjun Zhu, Hidayat R. Djajadi, Laurie L. Molday, Richard S. Smith, Richard T. Libby, Simon W. M. John, Robert S. Molday
Journal of Cell Science 2014 127: 1138-1149; doi: 10.1242/jcs.145052
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Research Article
Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival
Jonathan A. Coleman, Xianjun Zhu, Hidayat R. Djajadi, Laurie L. Molday, Richard S. Smith, Richard T. Libby, Simon W. M. John, Robert S. Molday
Journal of Cell Science 2014 127: 1138-1149; doi: 10.1242/jcs.145052

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