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Peer-reviewedCC BY-NC-NDInvestigative ophthalmology & visual science

Loss of Hippo Signaling Causes Coloboma via Steric Obstruction of Optic Fissure Fusion.

  • Uma M Neelathi1
  • Daniel Sanchez-Mendoza1
  • Sydney R Steele1
  • Rachel Aguda1
  • Brian P Brooks1
  1. 1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
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Abstract

Purpose

Pathogenic variants in the Hippo pathway effector YAP1 causes uveal coloboma in humans, a potentially blinding congenital eye malformation resulting from failure of optic fissure (OF) closure. Here, we characterize the pathogenesis of coloboma in zebrafish lacking the Hippo pathway effectors yap1 and wwtr1.Methods

OF closure and coloboma formation were studied in yap1bns19/bns19 and wwtr1bns35/bns35 mutant lines using histology and Laminin staining. The expression of yap1, wwtr1, and markers of ocular development, retinal pigment epithelium (RPE), and neural retina (NR) cell types was characterized by in situ hybridization or immunohistochemistry.Results

yap1 and wwtr1 are expressed in the developing RPE, including cells lining the OF, neural crest cells (NCC), and lens. yap1-/-; wwtr1+/- embryos develop coloboma, characterized by persistent Laminin staining, ventral pigmentation defects, loss of RPE markers, and pigmentation genes. Although patterning markers show similar expression patterns to controls, the OF markers ntn1a and pax2a indicate abnormal optic cup (OC) and fissure morphogenesis. Early retinal markers are misexpressed at the OF margins, whereas late NR markers are expressed between the OF edges, indicating differentiation of NR cells within the OF.Conclusions

Loss of yap1 and wwtr1 disrupts OC morphogenesis, preventing proper formation of the OF margins. We hypothesize that cells undergoing rim movement fail to integrate into the developing NR and instead remain between the OF edges, where they differentiate into NR tissue. This ectopic tissue forms a steric barrier that prevents OF fusion, resulting in coloboma.

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Cite

BibTeXRIS
BibTeX
@article{neelathi2026loss,
  title = {{Loss of Hippo Signaling Causes Coloboma via Steric Obstruction of Optic Fissure Fusion.}},
  author = {Uma M Neelathi and Daniel Sanchez-Mendoza and Sydney R Steele and Rachel Aguda and Brian P Brooks},
  journal = {Investigative ophthalmology \& visual science},
  year = {2026},
  month = oct,
  doi = {10.1167/iovs.67.12.22},
  url = {https://europepmc.org/article/MED/42872950},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Loss of Hippo Signaling Causes Coloboma via Steric Obstruction of Optic Fissure Fusion.
AU  - Uma M Neelathi
AU  - Daniel Sanchez-Mendoza
AU  - Sydney R Steele
AU  - Rachel Aguda
AU  - Brian P Brooks
PY  - 2026
DA  - 2026/10/01
JO  - Investigative ophthalmology & visual science
DO  - 10.1167/iovs.67.12.22
UR  - https://europepmc.org/article/MED/42872950
AB  - Purpose  Pathogenic variants in the Hippo pathway effector YAP1 causes uveal coloboma in humans, a potentially blinding congenital eye malformation resulting from failure of optic fissure (OF) closure. Here, we characterize the pathogenesis of coloboma in zebrafish lacking the Hippo pathway effectors yap1 and wwtr1.Methods  OF closure and coloboma formation were studied in yap1bns19/bns19 and wwtr1bns35/bns35 mutant lines using histology and Laminin staining. The expression of yap1, wwtr1, and markers of ocular development, retinal pigment epithelium (RPE), and neural retina (NR) cell types was characterized by in situ hybridization or immunohistochemistry.Results  yap1 and wwtr1 are expressed in the developing RPE, including cells lining the OF, neural crest cells (NCC), and lens. yap1-/-; wwtr1+/- embryos develop coloboma, characterized by persistent Laminin staining, ventral pigmentation defects, loss of RPE markers, and pigmentation genes. Although patterning markers show similar expression patterns to controls, the OF markers ntn1a and pax2a indicate abnormal optic cup (OC) and fissure morphogenesis. Early retinal markers are misexpressed at the OF margins, whereas late NR markers are expressed between the OF edges, indicating differentiation of NR cells within the OF.Conclusions  Loss of yap1 and wwtr1 disrupts OC morphogenesis, preventing proper formation of the OF margins. We hypothesize that cells undergoing rim movement fail to integrate into the developing NR and instead remain between the OF edges, where they differentiate into NR tissue. This ectopic tissue forms a steric barrier that prevents OF fusion, resulting in coloboma.
SN  - 0146-0404
SN  - 1552-5783
ER  -