Mice lacking Period 1 and Period 2 circadian clock genes exhibit blue cone photoreceptor defects

Authors

  • Ouafa Ait-Hmyed,

    1. Department of Neurobiology of Rhythms, CNRS UPR 3212, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
    2. Faculté des Sciences Semlalia, Laboratoire de Pharmacologie, Neurobiologie et Comportement, Université Cadi Ayyad, Marrakech, Morocco
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  • Marie-Paule Felder-Schmittbuhl,

    1. Department of Neurobiology of Rhythms, CNRS UPR 3212, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
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  • Marina Garcia-Garrido,

    1. Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
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  • Susanne Beck,

    1. Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
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  • Christina Seide,

    1. Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
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  • Vithiyanjali Sothilingam,

    1. Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
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  • Naoyuki Tanimoto,

    1. Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
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  • Mathias Seeliger,

    1. Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
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  • Mohammed Bennis,

    1. Faculté des Sciences Semlalia, Laboratoire de Pharmacologie, Neurobiologie et Comportement, Université Cadi Ayyad, Marrakech, Morocco
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  • David Hicks

    Corresponding author
    • Department of Neurobiology of Rhythms, CNRS UPR 3212, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
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Correspondence: Dr D. Hicks, as above.

E-mail: photoreceptor67@hotmail.com

Abstract

Many aspects of retinal physiology are modulated by circadian clocks, but it is unclear whether clock malfunction impinges directly on photoreceptor survival, differentiation or function. Eyes from wild-type (WT) and Period1 (Per1) and Period2 (Per2) mutant mice (Per1Brdm1Per2Brdm1) were examined for structural (histology, in vivo imaging), phenotypical (RNA expression, immunohistochemistry) and functional characteristics. Transcriptional levels of selected cone genes [red/green opsin (Opn1mw), blue cone opsin (Opn1sw) and cone arrestin (Arr3)] and one circadian clock gene (RORb) were quantified by real-time polymerase chain reaction. Although there were no changes in general retinal histology or visual responses (electroretinograms) between WT and Per1Brdm1Per2Brdm1 mice, compared with age-matched controls, Per1Brdm1Per2Brdm1 mice showed scattered retinal deformations by fundus inspection. Also, mRNA expression levels and immunostaining of blue cone opsin were significantly reduced in mutant mice. Especially, there was an alteration in the dorsal–ventral patterning of blue cones. Decreased blue cone opsin immunoreactivity was present by early postnatal stages, and remained throughout maturation. General photoreceptor differentiation was retarded in young mutant mice. In conclusion, deletion of both Per1 and Per2 clock genes leads to multiple discrete changes in retina, notably patchy tissue disorganization, reductions in cone opsin mRNA and protein levels, and altered distribution. These data represent the first direct link between Per1 and Per2 clock genes, and cone photoreceptor differentiation and function.

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