title: Effect of circadian clock gene mutations on nonvisual photoreception in the mouse.
abstract: OBJECTIVE
  Mice lacking rods and cones retain pupillary light reflexes that are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is necessary and sufficient for this nonvisual photoreception. The mammalian inner retina also expresses the potential blue light photopigments cryptochromes 1 and 2. Previous studies have shown that outer retinal degenerate mice lacking cryptochromes have lower nonvisual photic sensitivity than retinal degenerate mice, suggesting a role for cryptochrome in inner retinal photoreception.
  
  
  METHODS
  Nonvisual photoreception (pupillary light responses, circadian entrainment, and in vitro sensitivity of intrinsically photosensitive retinal ganglion cells) were studied in wild-type, rd/rd, and circadian clock-mutant mice with and without rd/rd mutation.
  
  
  RESULTS
  Loss of cryptochrome in retinal degenerate mice reduces the sensitivity of the pupillary light response at all wavelengths but does not alter the form of the action spectrum, suggesting that cryptochrome does not function as a photopigment in the inner retina. The authors compounded the rd/rd retinal degeneration mutation with mutations in other essential circadian clock genes, mPeriod and Bmal1. Both mPeriod1⁻/⁻; mPeriod2⁻/⁻;rd/rd and Bmal1⁻/⁻;rd/rd mice showed significantly lower pupillary light sensitivity than rd/rd mice alone. A moderate amplitude (0.5 log) circadian rhythm of pupillary light responsiveness was observed in rd/rd mice. Multielectrode array recordings of ipRGC responses of mCryptochrome1⁻/⁻;mCryptochrome2⁻/⁻ and mPeriod1⁻/⁻;mPeriod2⁻/⁻ mice showed minimal sensitivity decrement compared with wild-type animals. mCryptochrome1⁻/⁻;mCryptochrome2⁻/⁻;rd/rd, mPeriod1⁻/⁻;mPeriod2⁻/⁻;rd/rd and Bmal1⁻/⁻;rd/rd mice all showed comparable weak behavioral synchronization to a 12-hour light/12-hour dark cycle.
  
  
  CONCLUSIONS
  The effect of cryptochrome loss on nonvisual photoreception is due to loss of the circadian clock nonspecifically. The circadian clock modulates the sensitivity of nonvisual photoreception.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University Medical School, St. Louis, Missouri, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Owens
authors.forename: Ethan
authors.initials: E
authors.lastname: Buhr
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Tu
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.forename: Janet
authors.initials: J
authors.lastname: Lee
authors.forename: Russell N
authors.initials: RN
authors.lastname: Van Gelder
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D056931:Cryptochromes / Q000235:genetics; D005260:Female; D008027:Light; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D010775:Photic Stimulation; D012025:Reflex, Pupillary / Q000502:physiology*; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D014785:Vision, Ocular / Q000502:physiology*
chemical_list: C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes