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Heterozygous mutations in the FGF8, SHH and nodal/transforming growth factor beta pathways do not confer increased
Christine Lo1, Laura J Flinn, Oliver Bandmann
1Centre for Developmental and Biomedical Genetics-CDBG, Sheffield, UK.
Abstract:
Fibroblast growth factor 8 (FGF8), sonic hedgehog (SHH) and nodal signalling pathways play key roles in both development and survival of dopaminergic neurons. Both heterozygous mutations in autosomal recessively inherited Parkinson's disease (PD) genes such as parkin or PINK1 and exposure to exogenous toxins are thought to contribute to the pathogenesis of PD. The aim of our study was to investigate whether heterozygote mutations in fgf8, shh or oep lead to a reduced number of ascending dopaminergic neurons in zebrafish (Danio rerio) or confer increased susceptibility to the PD neurotoxin 1-methyl-4-phenyl-pyridinium (MPP⁺). At 3 days post fertilization, heterozygous mutations in fgf8, shh or oep did not affect the number of ascending dopaminergic neurons, nor did heterozygous mutations in fgf8, shh or oep result in increased susceptibility to MPP⁺. Further work is needed to determine whether haploinsufficiency in other neurodevelopmental genes might confer increased susceptibility to PD-related pathomechanisms.
Insights
Heterozygous mutations in fgf8, shh, or oep genes did not impact dopaminergic neuron development or increase susceptibility to Parkinson's disease toxins in zebrafish. Further research is needed on other neurodevelopmental genes.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Fibroblast growth factor 8 (FGF8), sonic hedgehog (SHH), and nodal signaling pathways are crucial for dopaminergic neuron development and survival.
- Parkinson's disease (PD) pathogenesis is linked to heterozygous mutations in PD genes (e.g., parkin, PINK1) and exposure to neurotoxins.
Purpose of the Study:
- To investigate if heterozygous mutations in fgf8, shh, or oep genes affect the number of ascending dopaminergic neurons in zebrafish.
- To determine if these mutations confer increased susceptibility to the PD neurotoxin 1-methyl-4-phenyl-pyridinium (MPP⁺).
Main Methods:
- Zebrafish (Danio rerio) models were used to study heterozygous mutations in fgf8, shh, and oep.
- Dopaminergic neuron counts were assessed at 3 days post fertilization.
- Susceptibility to MPP⁺ neurotoxin was evaluated in mutant zebrafish.
Main Results:
- Heterozygous mutations in fgf8, shh, or oep did not alter the number of ascending dopaminergic neurons at 3 days post fertilization.
- These mutations did not lead to increased susceptibility to MPP⁺-induced neurotoxicity in zebrafish.
Conclusions:
- Haploinsufficiency of fgf8, shh, or oep does not appear to contribute to the pathogenesis of Parkinson's disease through reduced dopaminergic neuron numbers or increased neurotoxin susceptibility in zebrafish.
- Further investigation into other neurodevelopmental genes is warranted to understand their potential role in PD susceptibility.
