Institute for Human Genetics, Biocenter, Julius-Maximilians-University, Würzburg, Germany.
Developmental Biology Unit, Institute of Zoology, University of Cologne, Cologne, Germany.
Sci Rep. 2020 Aug 7;10(1):13321. doi: 10.1038/s41598-020-70152-5.
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.
低磷酸酯酶症（HPP）是一种罕见的遗传性疾病，其症状多样，发病的严重程度也不同，其根本原因是 ALPL 基因的突变，该基因编码组织非特异性碱性磷酸酶（TNAP）。鉴于斑马鱼（Danio rerio）已被确立为 HPP 的新型模式生物，本研究旨在对胚胎和成年大脑中 alpl 的时空表达进行分析。此外，我们还确定了 Tnap 抑制对斑马鱼神经和骨骼发育的功能影响。研究结果表明，alpl 的表达存在于胚胎期和成年神经元组织中。对酶功能的分析揭示了在端脑和中脑存在着明显的 Tnap 活性区域。用化学 Tnap 抑制剂处理斑马鱼胚胎，然后对轴突和软骨/矿化组织进行染色，表明 Tnap 缺乏对神经元和骨骼发育有功能影响。基于对神经元和骨骼组织分析的结果，证明了该酶的进化保守作用，因此我们认为斑马鱼是一种很有前途的模式生物，可以用于长期发现新的潜在治疗策略。
