Abstract
Purpose: The rearranged during transfection (RET) receptor tyrosine kinase plays a key role in transducing signals related to cell growth and differentiation. Ret mutant mice show abnormal retinal activity and abnormal levels and morphology of bipolar cells, yet die on the 21st day after birth as a result of renal underdevelopment. To extend the observation period, we generated the Ret conditional knockout Chx10-Cre;C-Retlx/lx mouse model and analyzed the retinal function and morphological changes in mature and aging Chx10-Cre;C-Retlx/lx mice.Methods: Retina-specific depletion of Ret was achieved using mice with floxed alleles of the Ret gene with CHX10-driven Cre recombinase; floxed mice without Cre expression were used as controls. Retinal function was examined using electroretinography (ERG), and 2-, 4-, 12-, and 24-month-old mice were analyzed by hematoxylin staining and immunohistochemistry to evaluate retinal morphological alterations. The ultrastructure of photoreceptor synapses was evaluated using electron microscopy.Results: The results of the ERG testing showed that b-wave amplitudes were reduced in Chx10-Cre;C-Retlx/lx mice, whereas a-waves were not affected. A histopathological analysis revealed a thinner and disorganized outer plexiform layer at the ages of 12 and 24 months in Chx10-Cre;C-Retlx/lx mice. Moreover, the data provided by immunohistochemistry showed defects in the synapses of photoreceptor cells. This result was confirmed at the ultrastructural level, thus supporting the participation of Ret in the morphological changes of the synaptic ribbon.Conclusion: Our results provide evidence of the role of Ret in maintaining the function of the retina, which was essential for preserving the structure of the synaptic ribbon and supporting the integrity of the outer plexiform layer.
Highlights
The retina receives light signals at levels that span several orders of magnitude
We found that polymerase chain reaction (PCR) could amplify C-Ret in C-Retlx/lx retina, but barely in Chx10Cre;C-Retlx/lx retina, indicating that exon 12 of the C-Ret gene was deleted in most of the retina cells of Chx10-Cre;C-Retlx/lx mice (Figure 2A, top)
Because the Cre protein on its own has the capacity to cross the membrane and translocate to the nucleus (Will et al, 2002), the IHC results showed GFP expression only in the nuclei of Chx10-Cre;C-Retlx/lx bipolar cells, while PKCα expression was identified in the cytoplasm of bipolar cells in both C-Retlx/lx and Chx10-Cre;C-Retlx/lx mice (Figure 2B)
Summary
The retina receives light signals at levels that span several orders of magnitude. Adaptive changes to different light levels occur at multiple sites within the retinal signal transmission and act together in processing the light information. In contrast to conventional neurons, photoreceptors do not signal via action potentials; rather, they continuously translate light into a graded transmitter release, with the highest exocytosis rates in the dark To accomplish this task, photoreceptors and retinal bipolar cells contain a specialized type of synapse, the so-called ribbon synapse. The ribbon synapse is a specialized synaptic structure located in the outer plexiform layer (OPL) of the retina in which a synaptic “triad” is formed between the axonal pedicles of rods and cones and the dendrites of horizontal and bipolar cells Through this special synapse, visual signals are transmitted from photoreceptors to bipolar and horizontal cells (Heidelberger et al, 2005). Photoreceptor ribbon synapses play an important role in visual function
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