The zebrafish mutation m865 affects formation of dopaminergic neurons and neuronal survival, and maps to a genetic interval containing the sepiapterin reductase locus

Abstract

The zebrafish mutation m865 was isolated during a large-scale mutagenesis screen aimed at identifying genes involved in the development and maintenance of subgroups of neurons in the zebrafish central nervous system. The phenotype of m865 mutant embryos shows defects in the development of dopaminergic neurons in the pretectum and of retinal amacrine cells, as well as abnormal caudal dopaminergic cluster in the diencephalon. The effects of the mutation appear not to be restricted to dopaminergic neurons, as development of other neurotransmitter systems (serotonergic and cholinergic) is impaired as well. Furthermore, increased apoptosis is localized to the m865 mutant retina and in the optic tectum starting at 24hpf, and may lead to the observed reduced size of the mutant head and eye. Early patterning is not affected in m865 mutant embryos, and expression of genes known to play a role in dopaminergic cell differentiation is normal except for reduced expression of nurr1 in the mutant retina. Thus the m865 mutation does not specifically affect dopaminergic neuron development. m865 was genetically mapped to linkage group 5, and the critical genomic interval could be narrowed down to a region of 110 kb, containing four candidate genes. For one of these candidate genes, sepiapterin reductase (spr), a requirement for neuronal survival has previously been implicated, including dopaminergic neurons. Identification of the mutated gene should lead to a more detailed understanding of the defects observed in m865 mutant embryos, and potentially could enhance the understanding of the development and maintenance of specific dopaminergic neuronal populations.

The protein interactome of collapsin response mediator protein‐2 (CRMP2/DPYSL2) reveals novel partner proteins in brain tissue

“…One of the CRMP2 protein partners is SPR, which catalyzes the NADPH‐dependent reduction of pteridine derivatives for the production of tetrahydrobiopterin (BH4) .The latter is a cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, and nitric oxide synthase and, therefore, are important factors in neurotransmitter synthesis . SPR may also be involved in neuronal morphogenesis and deficiency of this protein has been implicated in dopa‐responsive dystonia . Since perturbations of dopaminergic pathways have been implicated as one of the main hypotheses in schizophrenia , the finding of differential expression of CRMP2 in brains from patients with this disorder should be studied further.…”

The Role of Zebrafish and Laboratory Rodents in Schizophrenia Research

“…In zebrafish, only one isoform of D3 and no D 5 receptor has been identified. In contrast, three isoforms of D 2 and D 4 receptors have been identified, at least some of which are encoded by distinct genes (D 2a , D 2b ) ( 47 , 148 , 149 ).…”

“…Complementary to rodent models were developed zebrafish genetic models of schizophrenia, including models studying contribution of genes encoding proteins involved in metabolism and function of individual neurotransmitters (tyrosine hydroxylase, D 4 receptor) or proteins controlling development (Disc1) (47)(48)(49)(50)(51).…”