AUTHOR=Peng Wei-Hao , Liao Meng-Lin , Huang Wan-Chun , Liu Pei-Kang , Levi Sarah R. , Tseng Yun-Ju , Lee Chia-Ying , Yeh Lung-Kun , Chen Kuan-Jen , Chien Chung-Liang , Wang Nan-Kai 

TITLE=Conditional Deletion of Activating Rearranged During Transfection Receptor Tyrosine Kinase Leads to Impairment of Photoreceptor Ribbon Synapses and Disrupted Visual Function in Mice

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.728905

DOI=10.3389/fnins.2021.728905

ISSN=1662-453X

ABSTRACT=<p><bold>Purpose:</bold> The rearranged during transfection (RET) receptor tyrosine kinase plays a key role in transducing signals related to cell growth and differentiation. <italic>Ret</italic> mutant mice show abnormal retinal activity and abnormal levels and morphology of bipolar cells, yet die on the 21<sup>st</sup> day after birth as a result of renal underdevelopment. To extend the observation period, we generated the <italic>Ret</italic> conditional knockout <italic>Chx10-Cre;C-Ret<sup><italic>lx/lx</italic></sup></italic> mouse model and analyzed the retinal function and morphological changes in mature and aging <italic>Chx10-Cre;C-Ret<sup><italic>lx/lx</italic></sup></italic> mice.</p><p><bold>Methods:</bold> Retina-specific depletion of <italic>Ret</italic> was achieved using mice with floxed alleles of the <italic>Ret</italic> 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.</p><p><bold>Results:</bold> The results of the ERG testing showed that b-wave amplitudes were reduced in <italic>Chx10-Cre;C-Ret<sup><italic>lx/lx</italic></sup></italic> 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 <italic>Chx10-Cre;C-Ret<sup><italic>lx/lx</italic></sup></italic> 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 <italic>Ret</italic> in the morphological changes of the synaptic ribbon.</p><p><bold>Conclusion:</bold> Our results provide evidence of the role of <italic>Ret</italic> 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.</p>