The Role of Wnt and BMP Signaling in Vertebrate Ocular Development and Disease

• Author / Creator

  Widen, Sonya

• Axial patterning of the developing vertebrate eye is crucial for proper axon pathfinding, as well as critically important morphogenetic events such as closure of the ocular fissure. Perturbations in eye morphogenesis can lead to ocular coloboma (failed ocular fissure closure) and microphthalmia (small eyes), together a leading cause of pediatric blindness. An exquisitely regulated balance of morphogen gradients, imparting positional information to retinal cells in order to regulate regionally restricted gene expression, performs patterning of the dorsal-ventral axis of the eye. This is achieved in large part through the complex and incompletely understood interactions between the bone morphogenetic protein (BMP), Wnt, and Sonic hedgehog (Shh) signaling pathways and the downstream factors they regulate.
  In this thesis, I have investigated the function of genes regulating both the BMP and Wnt signaling pathways in maintaining dorsal-ventral retinal identity, morphogenesis of the optic cup, and tissue fusion at the ocular fissure. I demonstrate that two members of a family of secreted Wnt inhibitors, sfrp1a and sfrp5, unexpectedly function to independently promote both Wnt and BMP signaling in the dorsal eye. Embryos with depleted Sfrp1a/5 display coloboma, likely due to aberrant gene expression observed across the dorsal-ventral axis of the eye.
  I assist in additionally characterizing a novel, conserved, highly transient fissure in the vertebrate dorsal eye and describe patients with a rare superior coloboma that results from incomplete dorsal fissure closure. Loss of dorsal BMP signaling, or increased Shh, alters the shape of the dorsal fissure and delays its closure. These data, combined with analyses of a BMP receptor mutation identified in a patient with superior coloboma, demonstrate that dorsal fissure formation and closure is also dependent upon proper dorsal-ventral retinal patterning.
  Finally, I identify and describe novel mutations that implicate two genes in causality of ocular coloboma and microphthalmia, the Wnt receptor FZD5 and BMP family member BMP3. In vitro assays suggest that the identified FZD5 mutation encodes a secreted dominant negative receptor and, combined with data from Fzd5-depleted zebrafish embryos, preliminarily indicate Fzd5 can mediate both canonical and non-canonical Wnt signaling in the eye. Initial characterization of bmp3 mutant zebrafish suggests a BMP- and patterning-independent role for Bmp3 and instead suggests it may directly regulate tissue fusion in the ocular fissure.

• Subjects / Keywords

  • Microphthalmia
  • Development
  • Coloboma
  • Wnt
  • Morphogenesis
  • BMP
  • Eye

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-sesz-hg76

• License

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