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1From the Laboratory for Retinal Cell Biology, Eye Clinic, University Hospital Zurich, Zurich, Switzerland.
PURPOSE. To test whether introduction of the Rpe65Leu450 variant can overcome protection against light-induced photoreceptor apoptosis in mice without the activator protein (AP)-1 constituent c-Fos.
METHODS. c-Fos-deficient mice (c-fos-/-) carrying the Leu450 variant of RPE65 were compared with c-fos-/- mice with Rpe65Met450. Expression of RPE65 was analyzed by Western blot analysis. Rhodopsin regeneration was determined by measuring rhodopsin after different times in darkness after bleaching. Susceptibility to light-induced damage was tested by exposure to white light and subsequent morphologic analysis. Activation of AP-1 and its complex composition was analyzed by electromobility shift assay (EMSA) and antibody interference. The contribution of AP-1 to apoptosis was tested by pharmacological inhibition of AP-1, using dexamethasone.
RESULTS. Compared with RPE65Met450, introduction of the RPE65Leu450 variant led to increased levels of RPE65 protein, accelerated rhodopsin regeneration, loss of protection against light-induced damage, and AP-1 responsiveness to toxic light doses, despite the absence of c-Fos. c-Fos was mainly replaced by Fra-2. Application of dexamethasone restored resistance to light-induced damage.
CONCLUSIONS. Increasing retinal photon catch capacity by introducing the Rpe65Leu450 variant overcomes light damage resistance provided by c-fos deficiency. Thus, a variation of RPE65 at position 450 is a strong genetic modifier of susceptibility to light-induced damage in mice. Under conditions of high rhodopsin availability during exposure to light, Fra-2 and, to a minor degree, FosB substitute for c-Fos and enable light-induced AP-1 activity and thus photoreceptor apoptosis. Regardless of the AP-1 complex’s composition, glucocorticoid receptor activation inhibits AP-1 and prevents apoptosis. Thus, not the absence of c-Fos per se, but rather impairment of AP-1 DNA binding is protective against light-induced damage. This impairment may result from the absence of c-Fos or glucocorticoid receptor-mediated transrepression.
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