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Background  The FERM domain containing protein Mosaic Eyes (Moe) interacts with Crumbs proteins, which are important regulators of apical identity and size. In zebrafish, loss-of-function mutations in  moe  result in defects in brain ventricle formation, retinal pigmented epithelium and neural retinal development, pericardial edema, and tail curvature. In humans and mice, there are two major alternately spliced isoforms of the Moe orthologue, Erythrocyte Protein Band 4.1-Like 5 (Epb4.1l5), which we have named Epb4.1l5 long  and Epb4.1l5 short , that differ after the FERM domain. Interestingly, Moe and both Epb4.1l5 isoforms have a putative C' terminal Type-I PDZ-Binding Domain (PBD). We previously showed that the N' terminal FERM domain in Moe directly mediates interactions with Crumbs proteins and Nagie oko (Nok) in zebrafish, but the function of the C'terminal half of Moe/Epb4.1l5 has not yet been examined.    Results  To define functionally important domains in zebrafish Moe and murine Epb4.1l5, we tested whether injection of mRNAs encoding these proteins could rescue defects in zebrafish  moe  -  embryos. Injection of either  moe  or  epb4.1l5   long   mRNA, but not  epb4.1l5   short   mRNA, could rescue  moe  -  embryonic defects. We also tested whether mRNA encoding C' terminal truncations of Epb4.1l5 long  or chimeric constructs with reciprocal swaps of the isoform-specific PBDs could rescue  moe  -  defects. We found that injection of the Epb4.1l5 short  chimera (Epb4.1l5 short+long_PBD ), containing the PBD from Epb4.1l5 long , could rescue retinal and RPE defects in  moe  -  mutants, but not brain ventricle formation. Injection of the Epb4.1l5 long  chimera (Epb4.1l5 long+short_PBD ), containing the PBD from Epb4.1l5 short , rescued retinal defects, and to a large extent rescued RPE integrity. The only construct that caused a dominant phenotype in wild-type embryos, was Epb4.1l5 long+short_PBD , which caused brain ventricle defects and edema that were similar to those observed in  moe  -  mutants. Lastly, the morphology of rod photoreceptors in  moe  -  mutants where embryonic defects were rescued by  moe  or  epb4.1l5   long   mRNA injection is abnormal and their outer segments are larger than normal.    Conclusion  Taken together, the data reveal tissue specificity for the function of the PBD in Epb4.1l5 long , and suggest that additional C' terminal sequences are important for zebrafish retinal development. Additionally, our data provide further evidence that Moe is a negative regulator of rod outer segment size.

Tissue-specific requirements for specific domains in the FERM protein Moe/Epb4.1l5 during early zebrafish development