title: The absence of melanopsin alters retinal clock function and dopamine regulation by light.
abstract: The retinal circadian clock is crucial for optimal regulation of retinal physiology and function, yet its cellular location in mammals is still controversial. We used laser microdissection to investigate the circadian profiles and phase relations of clock gene expression and Period gene induction by light in the isolated outer (rods/cones) and inner (inner nuclear and ganglion cell layers) regions in wild-type and melanopsin-knockout (Opn 4 (-/-) ) mouse retinas. In the wild-type mouse, all clock genes are rhythmically expressed in the photoreceptor layer but not in the inner retina. For clock genes that are rhythmic in both retinal compartments, the circadian profiles are out of phase. These results are consistent with the view that photoreceptors are a potential site of circadian rhythm generation. In mice lacking melanopsin, we found an unexpected loss of clock gene rhythms and of the photic induction of Per1-Per2 mRNAs only in the outer retina. Since melanopsin ganglion cells are known to provide a feed-back signalling pathway for photic information to dopaminergic cells, we further examined dopamine (DA) synthesis in Opn 4 (-/-) mice. The lack of melanopsin prevented the light-dependent increase of tyrosine hydroxylase (TH) mRNA and of DA and, in constant darkness, led to comparatively high levels of both components. These results suggest that melanopsin is required for molecular clock function and DA regulation in the retina, and that Period gene induction by light is mediated by a melanopsin-dependent, DA-driven signal acting on retinal photoreceptors.
authors.affiliation: Department of Chronobiology, INSERM U846, Stem Cell and Brain Research Institute, 18 Avenue du Doyen Lépine, 69500, Bron, France. ouria.benyahya@inserm.fr
authors.forename: Ouria
authors.initials: O
authors.lastname: Dkhissi-Benyahya
authors.forename: Christine
authors.initials: C
authors.lastname: Coutanson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Knoblauch
authors.forename: Hasna
authors.initials: H
authors.lastname: Lahouaoui
authors.forename: Vincent
authors.initials: V
authors.lastname: Leviel
authors.forename: Catherine
authors.initials: C
authors.lastname: Rey
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bennis
authors.forename: Howard M
authors.initials: HM
authors.lastname: Cooper
mesh_terms: D000818:Animals; D057906:Circadian Clocks; D002940:Circadian Rhythm; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D017299:Rod Opsins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099210:Melanopsin
chemical_list: D004298:Dopamine; D056950:Period Circadian Proteins; D017299:Rod Opsins; D014446:Tyrosine 3-Monooxygenase; D000099210:Melanopsin; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse