An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation [RESEARCH ARTICLE]

Melanie Rothe, Noreen Kanwal, Petra Dietmann, Franziska Seigfried, Annemarie Hempel, Desiree Schütz, Dominik Reim, Rebecca Engels, Alexander Linnemann, Michael J. Schmeisser, Juergen Bockmann, Michael Kühl, Tobias M. Boeckers, and Susanne J. Kühl

The signal-induced proliferation associated family of proteins comprises four members, SIPA1 and SIPA1L1-1L3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts up-stream of Sipa1l3 during eye development. Both, Sipa1l3 and Epha4 are required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax. We demonstrated that canonical Wnt signaling is inhibited downstream of Epha4/Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an up-regulation of axin2 expression, a direct Wnt/β-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/β-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells resulting in congenital cataracts.

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