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Published November 3, 2011 | public
Journal Article

Melanopsin signalling in mammalian iris and retina


Non-mammalian vertebrates have an intrinsically photosensitive iris and thus a local pupillary light reflex (PLR). In contrast, it is thought that the PLR in mammals generally requires neuronal circuitry connecting the eye and the brain. Here we report that an intrinsic component of the PLR is in fact widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment melanopsin; it also requires PLCβ4, a vertebrate homologue of the Drosophila Norp A phospholipase C which mediates rhabdomeric phototransduction. The Plcb4^(−/−) genotype, in addition to removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1 subtype of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (M1-ipRGCs), which are by far the most photosensitive ipRGC subtype and also have the largest response to light. Ablating in mouse the expression of both TRPC6 and TRPC7, members of the TRP channel superfamily, also essentially eliminated the M1-ipRGC light response but the intrinsic PLR was not affected. Thus, melanopsin signalling exists in both iris and retina, involving a PLCβ4-mediated pathway that nonetheless diverges in the two locations.

Additional Information

© 2011 Macmillan Publishers Limited. Received 11 May 2011. Accepted. 15 September 2011. Published online 02 November 2011. We thank the following individuals for providing knockout mouse lines: M. Caterina (Trpv42/2), J. Lem (Rho2/2 and Gnat12/2), J. C. Chen (Rho2/2), J. Nathans (cl, also known as cone-DTA), A. Sancar (Cry12/2Cry22/2) and L. Birnbaumer (Trpc12/2, Trpc32/2 and Trpc62/2). We thank D. Marshak, R. von der Heydt, X. Wang and V. Casagrande for eyes from baboon, rhesus monkey, marmoset and bush baby, respectively, and W. Li, R. Mi, B. O'Rourke, L. Pipitone, D. Ruben, D. Ryugo, L. Smale and G. Tomaselli for eyes of other animals. Experiments on bush baby were carried out in the Casagrande laboratory with help and hospitality. We also thank W. Gao for suggestions on the force transducer, F. Rieke and A. Sampath for suggestions on the design of the LED light system, P. Ala-Laurila for the method of equivalent 480-nm-photon conversion, H. Cahill for the mouse-head-anchoring method, X. Ren for help on western blots, O. Garalde and A. Chen for help in themonkey experiments, and W. W. S. Yue for help on RT–PCR. We also thank T. Shelley for fabricating all custom equipment, S. Kulason for help in data analysis, and L. Ding for mouse-genotyping support.Members of the Yau laboratory provided comments on the manuscript. This work was supported by US NIH Grant EY14596 and the Antόnio Champalimaud Vision Award (Portugal) to K.-W.Y. Author Contributions: T.X., M.T.H.D. and K.-W.Y. designed the experiments. T.X. and M.T.H.D. did the isolated-eyeball experiments. T.X. carried out all muscle recordings and also Trpc knockout ipRGC recordings at 23°C (recordings at 35u°C were by Z.J.), the mouse-optic-nerve transections, some of the in situ PLR measurements (the rest done by J.H.), some of the RT–PCR experiments on melanopsin (the rest done by H.C.W.), the tdTomato-fluorescence experiments, and the generation and maintenance of all double, triple and quadruple genetically engineered mouse lines for this study. The recordings from ipRGCs of Plcb42/2 mice and their wild-type littermates were done by M.T.H.D. (23°C) and Z.J. (35°C). T.X., M.T.H.D. and J.H. designed the head-fixed, dual-PLR-recording instrument. T.X. and H.C.W. did the anterior-chamber measurements. H.C.W. did the immunocytochemistry and X-gal labelling. S.L.M. and D.S.W. did the surgery of transecting the optic nerve in anaesthetized monkeys, and tested the PLR with T.X. and M.T.H.D. T.Y. participated in the monkey experiments. A.R. in D.E.C.'s laboratory made the Trpc72/2 mouse line and did the associated characterization (retinal RT–PCR done by T.X.). P.W., S.S., V.F. and M.F. made the Trpc52/2 line and did the associated characterization, and also provided the Trpc42/2 and Trpc42/2 Trpc52/2 lines. M.I.S. provided the Plcb42/2 line. T.X., M.T.H.D. and Z.J. analysed the data with assistance from J.H., and, together with K.-W.Y., wrote the paper.

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