Abstract
Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.
Highlights
Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissuenonspecific alkaline phosphatase (TNAP)
Transcript alignment of the zebrafish alpl gene with the human and mouse sequences revealed an identity of 61% and 63%, respectively
Additional synteny analysis further revealed that genes located in close proximity to the respective ALPL, Alpl, and alpl locus were showing a high level of genetic conservation between human, mouse, and zebrafish on the respective chromosomes 1, 4, or 11 (Fig. 1B; Genomicus v98.01 database)
Summary
Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissuenonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. The genetic cause of HPP are mutations in the ALPL gene, which encodes the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP). Apart from frequently occurring mineralization defects of bones and teeth, premature loss of deciduous teeth and craniosynostosis presuppose additional therapy for affected patients[1] Neurological symptoms such as epileptic seizures, depression, sleep- or anxiety-disorders further hamper HPP-patients’ quality of life[2]. Novel genetic and visualization techniques primarily established in zebrafish enable detailed cellular resolution of gene expression during brain development and open up the opportunity to image neural activity in freely behaving larvae[38,39]
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