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Zhijing Zhang, Alexia Vidal, Rachel Zimmerman, Christophe Ribelayga; A Circadian Clock in the Retina is Required for Normal Retinal Development and Visual Function. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5004.
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© ARVO (1962-2015); The Authors (2016-present)
Circadian clocks intrinsic to the retina are central regulators of retinal function. Although a clear link has been established between the presence of circadian clocks within the retina and retinal processing, the importance of these clocks in retinal development and visual function remain largely unknown. We studied the morphology and distribution of specific retinal cell types as well as aspects of visual behavior in a retina-specific circadian-clock-deficient mouse model at 2, 8 and 40 weeks of age.
A retina-specific circadian-clock-deficient mouse line was generated by conditionally silencing the essential circadian clock component Bmal1 in retinal cells using the Cre-loxP system. Specifically, we crossed Bmal1f/f mice with CHX10Cre mice. Immunohistochemistry was used to label cell markers and assay the expression of BMAL1 in retinal cells. Light entrainment and masking of the voluntary locomotor activity rhythm was tested using activity monitoring with wheeled cages. In addition, we measured spatial frequency threshold (i.e. acuity) and contrast sensitivity of freely moving mice by observing their optomotor responses to moving sine-wave gratings using the Optomotry system.
In the Bmal1f/f;CHX10Cre retina, BMAL1 was knocked-out in >99% of the cells. Compared to wild-type retinas, most cell types were present in the Bmal1f/f;CHX10Cre retinas but showed altered density and/or morphology. In addition, the Bmal1f/f;CHX10Cre retinas were thinner and their architecture showed gross lamination defects, including a “waveform”-like structure of the ONL. These defects were observed as early as 2 weeks of age, before the retina becomes fully mature (P20), indicating that they likely result from early developmental problems rather than maintenance/aging-related processes. In addition, we found that silencing clock activity in the retina impaired some aspects of visual function, including contrast sensitivity, but not acuity, as well as the negative masking of light on the locomotor activity rhythm.
Our data provide evidence that functional circadian clocks in the retina are required for normal retinal development and/or maintenance of normal visual function.
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