Rods and cones of the C57BL/6J mouse retina have been examined by light and electron microscopy to distinguish the structural features of the two photoreceptor types. By light microscopy, cone nuclei are conspicuously different from rod nuclei in 1-2 micrometer plastic sections. Cone nuclei have an irregularly shaped clump of heterochromatin that appears in single sections to be one to three clumps, whereas rod nuclei are more densely stained and have one large, central clump of heterochromatin. Cone nuclei make up approximately 3% of the photoreceptor nuclei in both the central and peripheral retina at all ages examined up to 267 days. Cone nuclei are confined to the outer half of the outer nuclear layer, and more than 50% of the cone nuclei lie adjacent to the outer limiting membrane. By electron microscopy, cones in the mouse retina meet virtually every morphological criterion of mammalian cones. The outer segments are conically shaped. Many, if not all of the outer segment discs are continuous with the outer plasma membrane, whereas almost all of the rod discs are not. Cone outer segments are only about half the length of the rod outer segments, and they are contacted by long, villous pigment epithelial cell processes. The cone inner segment diameter is greater than the outer segment diameter, and the accumulation of mitochondria present at the apical end of the inner segment forms a more conspicuous ellipsoid than in rods. The internal fiber or axon of the cone is larger in diameter than that of the rod, and it terminates in a large synaptic pedicle with multiple ribbon synapses, whereas the rod terminal is a smaller spherule with only a single ribbon synaptic complex.
The period of cell genesis of rod and cone photoreceptor cells has been determined in the retinas of C57BL/6J mice. Embryonic mice were exposed to a single dose of 3H-thymidine at embryonic day (E) 10--18 by injecting pregnant mice intraperitoneally. Animals at postnatal ages were injected subcutaneously once between postnatal day (P) 0--10. The eyes were removed at one to three months of age. After fixation, they were embedded in glycol methacrylate, sectioned at 1.5 micrometers and prepared for autoradiographic analysis. All of the cone cells are generated over a relatively short time interval during the fetal period. In the posterior retina, the peak of cone cell genesis occurs at E13-E14, and no cones are generated after E16. The rods, by contrast, are generated later and over a longer time period. They first begin to be generated in the posterior retina on E13, but the peak of cell genesis is not reached until the day of birth, and some rods are generated as late as P5. For both rods and cones the peaks of cell genesis in the peripheral retina occur two to three days later than in the posterior retina. The findings demonstrate that rods and cones are developmentally distinct cell types in the mouse retina.
Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A2B receptor (A2BR)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A2BR has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.
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