title: An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation.
abstract: The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. 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 upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.|International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm 89081, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rothe
authors.affiliation: International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm 89081, Germany.|Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Noreen
authors.initials: N
authors.lastname: Kanwal
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Dietmann
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.|International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm 89081, Germany.
authors.forename: Franziska A
authors.initials: FA
authors.lastname: Seigfried
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.|International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm 89081, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Hempel
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Desiree
authors.initials: D
authors.lastname: Schütz
authors.affiliation: International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm 89081, Germany.|Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Reim
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Engels
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Linnemann
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.|Department of Neurology, Ulm University, Ulm 89081, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schmeisser
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Bockmann
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kühl
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm 89081, Germany tobias.boeckers@uni-ulm.de susanne.kuehl@uni-ulm.de.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany tobias.boeckers@uni-ulm.de susanne.kuehl@uni-ulm.de.
authors.forename: Susanne J
authors.initials: SJ
authors.lastname: Kühl
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002386:Cataract / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004625:Embryo, Nonmammalian; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007908:Lens, Crystalline / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D011485:Protein Binding; D036122:Receptor, EphA4 / Q000378:metabolism / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D014981:Xenopus / Q000196:embryology / Q000235:genetics
chemical_list: D020690:GTPase-Activating Proteins; D036122:Receptor, EphA4
keywords: Epha4; Eye development; Sipa1l3; Spar3; Wnt; Xenopus