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Haruka Yamamoto, Yoshihiro Omori, Tetsuo Kon, Takahisa Furukawa; Functional diversity of Otx2 and Crx in retinal development. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6033.
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© ARVO (1962-2015); The Authors (2016-present)
Otx2 and Crx, members of the Otx homeobox gene family, are expressed in photoreceptor precursors and bind to the common DNA consensus sequence to control gene expression. However, the Otx2-deficient retina shows distinct phenotypes compared to those of the Crx-deficient retina. Otx2 begins to be expressed in developing photoreceptors earlier than Crx. It is not clear whether the functional difference between Otx2 and Crx in retinal development is due to the differences in the nature of the proteins or in the timing of gene expression in developing photoreceptors. Moreover, Otx2 is strongly expressed in bipolar cells at postnatal stages. We analyzed common and different roles between Otx2 and Crx in photoreceptor and bipolar cell development.
To test the possibility of replacing Otx2 with Crx and vice versa in photoreceptor cell fate determination and maturation in vivo, we generated Crx knock-in (KI) mice in which Crx cDNA is inserted into the Otx2 locus and Otx2 KI mice in which Otx2 cDNA is inserted into the Crx locus. In addition, to investigate whether the expression levels of Otx2 affects the cell fate determination in photoreceptor and bipolar cells, we performed lineage analyses of Otx2 overexpression and knockdown retinas using retrovirus vectors. Moreover, we generated ON-bipolar specific Otx2 conditional knockout (CKO) mice using Grm6-Cre transgenic mice.
In the immunohistochemical analysis, the Crx KI retina showed no significant difference compared to the Otx2-deficient retina. The Otx2 KI retinas showed a disorganization of the outer segment and synaptic formation as well as the Crx-deficient retinas. On the other hand, the Otx2 KI retinas decreased apoptotic cell death compared to the Crx-deficient retinas in photoreceptor maintenance. Exogenous Otx2 expression seems to partially suppress apoptotic cell death in photoreceptor maintenance caused by the loss of Crx. Lineage analysis showed that relatively high levels of Otx2 induced photoreceptor cell fate, but relatively low levels of Otx2 weakly induced amacrine cell fate. ON-bipolar-specific Otx2 CKO mice showed that ON-bipolar cells were totally lost.
Our results suggest that the protein functions of Crx and Otx2 partially overlap in photoreceptor cell survival but not in photoreceptor cell fate and maturation. On the other hand, it was suggested that Otx2 is essential for the ON bipolar cell maturation but not for bipolar cell fate.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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