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首页> 外文期刊>Genomics >Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes.
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Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes.

机译：小鼠酸性神经酰胺酶基因的插入诱变导致纯合子的早期胚胎致死率和杂合子的进行性脂质贮积病。

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摘要

Ceramide is an important cellular lipid involved in signal transduction and the biosynthesis of complex sphingolipids. It can be hydrolyzed into sphingosine, another important signaling lipid, by the activity of ceramidases. Point mutations in the gene (Asah1) encoding one ceramidase, acid ceramidase (AC), lead to the lysosomal storage disorder Farber disease (FD). To investigate the role of AC in mammalian development, we disrupted the mouse gene Asah1 in embryonic stem cells by homologous recombination mediated insertion of an AC targeting vector into the wild-type sequence. Genotype analysis of over 150 offspring or embryos from heterozygous intercrosses revealed an absence of Asah1(-/-) individuals at embryonic day (E) 8.5 or later, although the ratio of wild-type to Asah1(+/-) individuals from these intercrosses was 1:2. Northern blot analysis showed that AC expression was turned on early in development, by E7.0, and continued through at least E17. In contrast, expression of the related lipid hydrolase, acid sphingomyelinase, was shut down by E11. Asah1(+/-) mice survived and lived a normal lifespan, but developed a progressive lipid storage disease in several of their organs, particularly the liver. These histopathological findings in Asah1(+/-) animals correlated with an up to twofold increase in the ceramide content of these tissues and a reduction n AC activity, confirming that the gene insertion event disrupted AC activity and ceramide metabolism. These results provide direct in vivo evidence that normal ceramide metabolism, and AC activity in particular, is essential for mammalian development. The animals and embryos described here should be a valuable resource for investigators studying the role of ceramide in cell growth and development, as well as those interested in the pathogenesis of FD and other sphingolipid storage disorders.
机译：神经酰胺是一种重要的细胞脂质，参与信号转导和复杂鞘脂的生物合成。它可以通过陶瓷酶的活性水解为鞘氨醇，另一种重要的信号脂质。编码一种神经酰胺酶，酸性神经酰胺酶（AC）的基因（Asah1）中的点突变导致溶酶体贮积病法伯病（FD）。为了研究AC在哺乳动物发育中的作用，我们通过同源重组介导的AC靶向载体插入野生型序列，破坏了胚胎干细胞中的小鼠基因Asah1。对150多个杂合子交配的后代或胚胎的基因型分析显示，在胚胎天（E）8.5或更晚时，没有Asah1（-/-）个体，尽管这些交配的野生型与Asah1（+/-）个体的比率是1：2。 Northern印迹分析表明AC表达在发育早期由E7.0开启，并持续至少E17。相反，E11关闭了相关脂质水解酶酸性鞘磷脂酶的表达。 Asah1（+/-）小鼠存活下来并过着正常的寿命，但是在其多个器官，特别是肝脏中发展为进行性脂质存储疾病。在Asah1（+/-）动物中的这些组织病理学发现与这些组织中神经酰胺含量的最高增加两倍和n AC活性的降低相关，证实基因插入事件破坏了AC活动和神经酰胺代谢。这些结果提供了直接的体内证据，证明正常的神经酰胺代谢，特别是AC活性对于哺乳动物的发育至关重要。这里描述的动物和胚胎对于研究者神经酰胺在细胞生长和发育中的作用以及对FD和其他鞘脂贮积症的发病机制感兴趣的研究者而言，应该是宝贵的资源。

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