Impaired dopaminergic neuron development and locomotor function in zebrafish with loss of pink1 function.
Mutations in the human PTEN-induced kinase 1 (PINK1) gene are linked to recessive familial Parkinson's disease. Animal models of altered PINK1 function vary greatly in their phenotypic characteristics. Drosophila pink1 mutants exhibit mild dopaminergic neuron degeneration and locomotion defects. Such defects are not observed in mice with targeted null mutations in pink1, although these mice exhibit impaired dopamine release and synaptic plasticity. Here, we report that in zebrafish, morpholino-mediated knockdown of pink1 function did not cause large alterations in the number of dopaminergic neurons in the ventral diencephalon. However, the patterning of these neurons and their projections are perturbed. This is accompanied by locomotor dysfunction, notably impaired response to tactile stimuli and reduced swimming behaviour. All these defects can be rescued by expression of an exogenous pink1 that is not a target of the morpholinos used. These results indicate that normal PINK1 function during development is necessary for the proper positioning of populations of dopaminergic neurons and for the establishment of neuronal circuits in which they are implicated.
Xi
Yanwei
Y
Center for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, 30 Marie Curie, Ottawa, Ontario, Canada K1N6N5.
Ryan
Joel
J
Noble
Sandra
S
Yu
Man
M
Yilbas
Ayse E
AE
Ekker
Marc
M
D000595:Amino Acid Sequence; D000818:Animals; D004027:Diencephalon / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D013550:Swimming / Q000502:physiology*; D055698:Touch Perception / Q000502:physiology*; D015027:Zebrafish; D000099202:PTEN-Induced Putative Kinase
D004298:Dopamine; D016376:Oligonucleotides, Antisense; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase