Mice lacking Period 1 and Period 2 circadian clock genes exhibit blue cone photoreceptor defects.
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 (Per1(Brdm1) Per2(Brdm1) ) 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 Per1(Brdm1) Per2(Brdm1) mice, compared with age-matched controls, Per1(Brdm1) Per2(Brdm1) 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.
Department of Neurobiology of Rhythms, CNRS UPR 3212, Institut des Neurosciences Cellulaires et Intégratives, 5 rue Blaise Pascal, 67084, Strasbourg, France.
Ouafa
O
Ait-Hmyed
Marie-Paule
MP
Felder-Schmittbuhl
Marina
M
Garcia-Garrido
Susanne
S
Beck
Christina
C
Seide
Vithiyanjali
V
Sothilingam
Naoyuki
N
Tanimoto
Mathias
M
Seeliger
Mohammed
M
Bennis
David
D
Hicks
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2 / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D019390:Arrestins; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D017299:Rod Opsins; C539741:Rorb protein, mouse; C095854:middle-wavelength opsin; C095853:short-wavelength opsin