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.

Nosip functions during vertebrate eye and cranial cartilage development

“…Area of eyes was measured using the ImageJ64 software (Wayne Rasband) (Kiem et al, 2017;Rothe et al, 2017). Area of eyes was measured using the ImageJ64 software (Wayne Rasband) (Kiem et al, 2017;Rothe et al, 2017).…”

“…Unilaterally Control or Nosip MO injected embryos at stage 42 of one representative experiment were photographed for eye measurement. Area of eyes was measured using the ImageJ64 software (Wayne Rasband) (Kiem et al, 2017;Rothe et al, 2017).…”

Phenogenon: Gene to Phenotype Associations for Rare Genetic Diseases

“…SIPA1L3 (OMIM: 616655), a gene associated with recessive congenital cataract, was found to have a high HGF score on Abnormal electroretinogram (HGF: 10.66) and Rod-cone dystrophy (HGF: 7.45), with dominant MOI. Although no SIPA1L3 mutations have been reported with relevance to retinal dystrophy, it was found to be highly expressed in Xenopus laevis retina 37 , indicating a link between this gene and retina disorders. ATG16L1 , known to cause Crohn disease, was linked to 'Severe combined immunodeficiency'.…”

Modeling ocular lens disease in Xenopus

“…Knocking‐down sparc with antisense morpholinos in Xenopus results in a high mortality due to defective cell‐cell adhesion after gastrulation, but surviving tailbuds injected with a reduced amount of morpholino display poorly characterized lens phenotypes evocative of cataract . Knocking‐down the orthologues of mammalian cataract genes like TMEM114 , CHRLD1 , SIPAL3 or CELF1 produces eye phenotypes generally loosely related to cataract . Hence, whether ocular lens developmental defects, including cataract, can be modeled in Xenopus remains an open question.…”