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
  • Animals
  • Hedgehog Proteins*/genetics
  • Hedgehog Proteins*/metabolism
  • Gene Expression Regulation, Developmental
  • Signal Transduction*
  • Netrins/genetics
  • Netrins/metabolism
  • Netrin-1/genetics
  • Netrin-1/metabolism
  • Zebrafish*/embryology
  • Coloboma/genetics
  • Coloboma/metabolism
  • Eye/embryology
  • Eye/metabolism
  • Patched-2 Receptor/genetics
  • Patched-2 Receptor/metabolism
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
(all 18)
PubMed
39166841 Full text @ Dev. Dyn.
Abstract
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.
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.
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
Marker Marker Type Name
ntn1aGENEnetrin 1a
ntn1bGENEnetrin 1b
ntn2GENEnetrin 2
ntn4GENEnetrin 4
ntn5GENEnetrin 5
ptch2GENEpatched 2
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Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
p210
    Unknown
    tc294z
      Unknown
      z200TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        ntn1aCRISPR4-ntn1aCRISPR
        ntn1aMO5-ntn1aMRPHLNO
        ntn2CRISPR1-ntn2CRISPR
        ntn5CRISPR1-ntn5CRISPR
        1 - 4 of 4
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        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        1 - 1 of 1
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        Mapping
        No data available