Interestingly, the effects of GFRα4 on photoreceptors in retinal spheres reflects some but not all characteristics of human enhanced S-cone syndrome. Patients with this syndrome show an increased number of S-cones (also referred to as blue cones), whereas middle- and long-wavelength cone and rod function are dramatically decreased.
37 38 An increase of S-cones has also been shown in mice lacking the neural retina leucin (Nrl) zipper.
39 Additionally, defects in other transcriptional regulators, such as Crx and Nr2e3, caused similar effects on photoreceptor differentiation, especially on the determination of blue cones.
37 Although it has been shown that several transcription factors, such as Crx, NeuroD, Nrl, and Nr2e3, are involved in the regulation of rod cell fate, little is known about factors necessary for the differentiation of S- and M-cones.
40 Interestingly, in a recent study,
41 it has been shown that in the retinal degeneration (rd7) mutant mouse, a model for the human enhanced S-cone syndrome, nearly all photoreceptors expressed cone- and rod-specific genes, representing a hybrid photoreceptor type. These results indicate that the mutation in Nr2e3 was able to regulate the expression of rod- and cone-specific genes. Moreover, especially in the context of green and blue cone cell fate determination, it is known that at least for mice and rats, blue opsins are synthesized in prospective green cones before the expression of green opsins.
42 Because the developing immature cones of mice are able to express blue cone opsins but not green cone opsins, it has been suggested that the expression of blue opsins probably represents a default pathway of opsin expression.
43 44 45 Interestingly, it has been suggested that the blue-to-green switch in rodents probably correlates with the synthesis of rhodopsin expression in immature rods and that the regulation of cone- and rod-specific genes through the photoreceptor-specific nuclear receptor (PNR) or the orphan nuclear receptor transcription factor (Nr2e3) are somehow linked. In this context, it is thought that GFRα4 signaling is one possible upstream component of the PNR signaling pathway or that GFRα4 probably is involved in the regulation of the PNR and Nr2e3 pathways. In summary, we have demonstrated by siRNA-mediated gene silencing that GFRα4 is involved in the regulation of proliferation and differentiation of cells born early in retinogenesis. In addition to the reduction of Pax 6-positive cells, it is likely that GFRα4 signaling is essential for the determination of blue- and green-sensitive photoreceptors in the chicken retina.