Heterozygous mutations in the FGF8, SHH and nodal/transforming growth factor beta pathways do not confer increased dopaminergic neuron vulnerability—A zebrafish study

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.

► Zebrafish are a powerful vertebrate model to study human disease.
► Neurodevelopmental pathways might contribute to pathogenesis of Parkinson's disease.
► FGF8, SHH and nodal pathways are crucial for survival of dopaminergic neurons.
► Heterozygote mutations in these pathways do not lead to increased dopaminergic neuron vulnerability.