PUBLICATION
Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation
- Authors
- Lusk, S., LaPotin, S., Presnell, J.S., Kwan, K.M.
- ID
- ZDB-PUB-240822-6
- Date
- 2024
- Source
- Developmental Dynamics : an official publication of the American Association of Anatomists : (Journal)
- Registered Authors
- Kwan, Kristen
- Keywords
- coloboma, eye development, morphogenesis, netrin1a, ptch2
- MeSH Terms
-
- Patched-2 Receptor/genetics
- Patched-2 Receptor/metabolism
- Netrins/genetics
- Netrins/metabolism
- Coloboma/genetics
- Coloboma/metabolism
- Eye/embryology
- Eye/metabolism
- Hedgehog Proteins*/genetics
- Hedgehog Proteins*/metabolism
- Gene Expression Regulation, Developmental
- Animals
- Zebrafish*/embryology
- Signal Transduction*
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Netrin-1/genetics
- Netrin-1/metabolism
- PubMed
- 39166841 Full text @ Dev. Dyn.
Citation
Lusk, S., LaPotin, S., Presnell, J.S., Kwan, K.M. (2024) Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation. Developmental Dynamics : an official publication of the American Association of Anatomists. :.
Abstract
Background Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor ptch2 produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes.
Results We find multiple Netrin ligands upregulated in the zebrafish ptch2 mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that netrin1a or netrin1b overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the ptch2 mutant: loss of netrin genes does not rescue the ptch2 mutant phenotype.
Conclusion These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the ptch2 mutant.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping