title: Isoforms of Melanopsin Mediate Different Behavioral Responses to Light.
abstract: Melanopsin (OPN4) is a retinal photopigment that mediates a wide range of non-image-forming (NIF) responses to light including circadian entrainment, sleep induction, the pupillary light response (PLR), and negative masking of locomotor behavior (the acute suppression of activity in response to light). How these diverse NIF responses can all be mediated by a single photopigment has remained a mystery. We reasoned that the alternative splicing of melanopsin could provide the basis for functionally distinct photopigments arising from a single gene. The murine melanopsin gene is indeed alternatively spliced, producing two distinct isoforms, a short (OPN4S) and a long (OPN4L) isoform, which differ only in their C terminus tails. Significantly, both isoforms form fully functional photopigments. Here, we show that different isoforms of OPN4 mediate different behavioral responses to light. By using RNAi-mediated silencing of each isoform in vivo, we demonstrated that the short isoform (OPN4S) mediates light-induced pupillary constriction, the long isoform (OPN4L) regulates negative masking, and both isoforms contribute to phase-shifting circadian rhythms of locomotor behavior and light-mediated sleep induction. These findings demonstrate that splice variants of a single receptor gene can regulate strikingly different behaviors.
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK; F. Hoffmann-La Roche AG, Pharma Research and Early Development, DTA Neuroscience pRED, Grenzacherstrasse 124, Basel 4070, Switzerland.
authors: Aarti
authors: A
authors: Jagannath
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK; F. Hoffmann-La Roche AG, Pharma Research and Early Development, DTA Neuroscience pRED, Grenzacherstrasse 124, Basel 4070, Switzerland.
authors: Steven
authors: S
authors: Hughes
authors: Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK.
authors: Amr
authors: A
authors: Abdelgany
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Carina A
authors: CA
authors: Pothecary
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Simona
authors: S
authors: Di Pretoro
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Susana S
authors: SS
authors: Pires
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Athanasios
authors: A
authors: Vachtsevanos
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Violetta
authors: V
authors: Pilorz
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Laurence A
authors: LA
authors: Brown
authors: Axolabs GmbH, Fritz-Hornschuch-Straße 9, 95326 Kulmbach, Germany.
authors: Markus
authors: M
authors: Hossbach
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Robert E
authors: RE
authors: MacLaren
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Stephanie
authors: S
authors: Halford
authors: F. Hoffmann-La Roche AG, Pharma Research and Early Development, DTA Neuroscience pRED, Grenzacherstrasse 124, Basel 4070, Switzerland.
authors: Silvia
authors: S
authors: Gatti
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK.
authors: Mark W
authors: MW
authors: Hankins
authors: Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK.
authors: Matthew J A
authors: MJ
authors: Wood
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK. Electronic address: russell.foster@eye.ox.ac.uk.
authors: Russell G
authors: RG
authors: Foster
authors: Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, University of Oxford, Levels 5-6 West Wing, Headley Way, Oxford OX3 9DU, UK. Electronic address: stuart.peirson@eye.ox.ac.uk.
authors: Stuart N
authors: SN
authors: Peirson
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002940:Circadian Rhythm; D006801:Humans; D008027:Light; D051379:Mice / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009043:Motor Activity; D010470:Perceptual Masking; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011680:Pupil / Q000502:physiology* / Q000528:radiation effects; D017299:Rod Opsins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012890:Sleep; D000099210:Melanopsin
chemical_list: D020033:Protein Isoforms; D017299:Rod Opsins; D000099210:Melanopsin