The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and cone cells are not required for photoentrainment. Recent evidence suggests that the entraining photoreceptors are retinal ganglion cells (RGCs) that project to the SCN. The visual pigment for this photoreceptor may be melanopsin, an opsin-like protein whose coding messenger RNA is found in a subset of mammalian RGCs. By cloning rat melanopsin and generating specific antibodies, we show that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat RGCs. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, β-galactosidase-positive RGC axons projected to the SCN and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat RGCs that exhibited intrinsic photosensitivity invariably expressed melanopsin. Hence, melanopsin is most likely the visual pigment of phototransducing RGCs that set the circadian clock and initiate other non-image-forming visual functions.Retinal rods and cones, with their light-sensitive, opsin-based pigments, are the primary photoreceptors for vertebrate vision. Visual signals are transmitted to the brain through RGCs, the output neurons whose axons form the optic nerve. This system, through its projections to the lateral geniculate nucleus and the midbrain, is responsible for interpreting and tracking visual objects and patterns. A separate visual circuit, running in parallel with this imageforming visual system, encodes the general level of environmental illumination and drives certain photic responses, including synchronization of the biological clock with the light-dark cycle (1), control of pupil size (2), acute suppression of locomotor behavior (3), melatonin release (4), and others (5-7). Surprisingly, this non-image-forming system does not appear to originate from rods and cones. For example, rods and cones are not required for photoentrainment of circadian rhythms (8), a function mediated by the retinohypothalamic tract (9,10) and its target, the SCN, the brain's circadian pacemaker (1). Nor are rods and cones necessary for the pupillary light reflex, mediated by the retinal projection to the pretectal region of the brainstem (2). At present, the best candidate for a photopigment is an opsin-like protein † To whom correspondence should be addressed. kwyau@mail.jhmi.edu. * These authors contributed equally to this work. called melanopsin, which is expressed by a subset of mouse and human RGCs (11). The accompanying report (12) shows that RGCs projecting to the SCN are directly sensitive to light. Thus, melanopsin may be the photopigment responsible for this intrinsic photosensitivity, and it may also trigger other non-image-forming visual functions.
NIH Public AccessWe cloned the full-length cDNA for rat melanopsin (13), on the basis of homology to mouse melanopsin (11). The predicted amino...