experiments indicated that at least some cones express only a single type of pigment. These features of the cone mosaic will profoundly influence the kinds of visual information that the mouse is able to extract from retinal illumination. Some of these issues are considered next.

Expression of Mouse Cone Pigments

The processes determining which opsin gets expressed in individual cones are not well understood. The mouse retina, with its clear spatial gradient of M and UV pigment expression and with extensive pigment coexpression (implying a failure of the selection mechanism), provides a useful arena in which to examine the details of cone opsin expression. Interest here necessarily focuses on events occurring early in retinal development. Observations made on a number of species suggest that during development SWS1 pigments are expressed prior to the appearance of cone pigments specified by LWS genes. In young mice, for example, cones containing UV pigment can be detected approximately a week before M pigment first appears [29]. More generally, it has been suggested that expression of S/UV pigments represents a default pathway such that the presence of a timed signal is required to induce cones to express M/L pigments [9]. One line of evidence suggests that thyroid hormone may be the signal. The thyroid hormone receptor β2 is found only in cone receptors, where it is believed to regulate gene transcription. When this receptor is deleted, mouse retinas show a selective loss of M cones and a concomitant increase in UV cones [30]. An examination of the role of thyroid hormone availability on the expression of mouse cone pigments provides additional insight. Treatment of retinal explants with exogenous thyroid hormone causes a dose-dependent decrease in UV-expressing cones, while at the same time there is an increase in the abundance of M cones [31]. Further, a dorsal-ventral gradient of thyroid hormone can be detected at the stage in development when M pigment begins to appear, with hormone levels highest in the dorsal retina. These studies thus suggest that thyroid hormone is important for establishing cone opsin patterning across the mouse retina and, by extension, may have an analogous role in all mammalian retinas.

Given that the thyroid hormone receptor β2 seems essential for M opsin expression, which factors are required to trigger the expression of mouse UV opsin? An experiment suggested a role for an orphan nuclear receptor called retinoid-related orphan receptor β (RORβ) [32]. Various lines of evidence from this investigation suggested that RORβ, which is abundantly expressed in brain and pineal gland as well as in the retina, activates the upstream promoter sequence of the SWS1 opsin gene during cone photoreceptor development, thus directing UV pigment expression. The evidence includes the facts that (1) there are functional binding sites for RORβ, (2) RORβ actually binds to these sites, and (3) the induction of UV opsin is greatly impaired in mice engineered to lack these binding sites. Presumably, the timing of expression of UV opsin is then linked to the changing levels and patterns of thyroid hormone as described.

CONE SIGNAL PATHWAYS IN THE MOUSE RETINA

Significant advances have been made in identifying the constituent cells of the mammalian retina, in analyzing the interconnections of these cells, and in detailing the

retinal pathways through which photoreceptor signals are eventually collated and analyzed (for reviews, see [33, 34]). Two major generalizations have emerged. First, with the exception of specializations that are characteristic of the primate fovea, there is a considerable conservation in the number of cell types and in the pattern of retinal wiring across all mammals. Thus, all mammalian retinas feature a series of parallel circuits that originate in the photoreceptors and pass through the retina via intermediary cells to converge onto 10–15 separate types of ganglion cell. Second, even though rods greatly outnumber cones in most mammalian retinas, the network of postreceptoral cells transmitting cone signals is elaborate relative to the circuitry dedicated to processing rod-based signals. For example, there are 9–11 types of mammalian bipolar cells driven by cones, whereas these same retinas typically have only a single type of bipolar cell dedicated exclusively to the transmission of rod inputs [33]. This last fact is in accord with the view that during the diversification of vertebrate eyes the rod system was simply engrafted onto a cone-based system that had evolved earlier.

Whereas the structural organization of the cone pathways in the mouse retina seems generally consistent with the principles just mentioned [7], the regionalization of cone pigments and the variable coexpression of these pigments in individual cones greatly complicate the understanding of nature of cone signals one might expect to see in the mouse retina. For example, a conserved feature of mammalian retinas is the presence of a class of bipolar cells (usually called S-cone ON bipolars) connected through a signinverting synapse to short-wavelength-sensitive cones. Normally, the outputs from such bipolars converge onto ganglion cells along with opposite-sign signals delivered via a class of bipolar cells connected to cones containing middleand long-wavelength- sensitive pigments [33]. The net result is a ganglion cell that responds in a chromatically opponent fashion (i.e., inhibiting to some wavelengths of light and exciting to others) and thus stands in position to signal onward information that can be used to support a dimension of color vision. If, however, all cones coexpress both shortand longwavelength pigments, as some allege they do in the mouse, then the spectral sensitivities of the contrasting inputs to the ganglion cell will not differ, so that ganglion cell spectral opponency (and, hence, a potential color signal) may be effectively obviated.

Given the current uncertainties about the extent and nature of cone pigment coexpression, what actually happens in the cone pathways of the mouse retina is not clear. Based on the observation that the relationship between mouse spectral sensitivity measured in the outer retina and by behavioral means is unusual, it was suggested that, although there is variable coexpression of cone pigments in the mouse retina, the connections made by mouse cones are similar to the typical mammalian pattern, implying that the signals from the majority of those cones that coexpress pigment are connected in the same fashion as is typical of long-wavelength cones in mammalian retinas. Consequently, the convergence of signals onto the ganglion cells of the type under discussion is largely of the nature of UV − (M + UV) [35]. Such cells could yield a significantly muted, but still spectrally opponent, signal. A recent investigation employing markers that made it possible to label UV-cone bipolar cells as well as identify their cone inputs supported this possibility. Indeed, that study concluded that these bipolar cells show the same selectively in their cone contacts as seen in other mammalian retinas; that is, they contact only cones containing UV pigment [27].