Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation.
Dev Dyn
; 2024 Aug 21.
Article
in En
| MEDLINE
| ID: mdl-39166841
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Dev Dyn
Journal subject:
ANATOMIA
Year:
2024
Document type:
Article
Affiliation country:
United States
Country of publication:
United States