Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome
Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome
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DOI：
10.1073/pnas.1006437108
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发表时间：
2011-08-02
影响因子：
11.1
通讯作者：
Murtaugh, L. Charles
中科院分区：
文献类型：
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作者：
Barrott, Jared J.;Cash, Gabriela M.;Murtaugh, L. Charles
果蝇豪猪基因是分泌无翅蛋白和其他Wnt蛋白所必需的，其独特的人类直系同源物PORCN中的零星突变引起多效性X连锁显性疾病，局灶性皮肤发育不全（FDH，也称为Goltz综合征）。我们产生了一个条件等位基因的X-连锁小鼠Porcn基因，并分析其在Wnt信号和胚胎发育的要求。我们发现Porcn缺陷细胞在Wnt配体分泌方面表现出细胞自主缺陷，但对外源性Wnt仍有反应。与FDH的雌性特异性遗传模式一致，Porcn半合子雄性胚胎在早期胚胎发生期间停滞并且未能产生中胚层，这是先前与Wnt活性丧失相关的表型。杂合子Porcn突变型女性表现出一系列肢体、皮肤和身体模式异常，类似于在FDH患者中观察到的异常。这些缺陷中的许多被Porcn的外胚层特异性缺失所概括，证实了关于人FDH病因学的长期假设，并扩展了以前的研究，这些研究集中在Wnt信号传导的下游元件，如β-连环蛋白。因此，Porcn的条件性缺失提供了FDH的实验模型，以及在体内探测Wnt配体功能的有价值的工具。
The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN, cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts. Consistent with the female-specific inheritance pattern of FDH, Porcn hemizygous male embryos arrest during early embryogenesis and fail to generate mesoderm, a phenotype previously associated with loss of Wnt activity. Heterozygous Porcn mutant females exhibit a spectrum of limb, skin, and body patterning abnormalities resembling those observed in human patients with FDH. Many of these defects are recapitulated by ectoderm-specific deletion of Porcn, substantiating a long-standing hypothesis regarding the etiology of human FDH and extending previous studies that have focused on downstream elements of Wnt signaling, such as beta-catenin. Conditional deletion of Porcn thus provides an experimental model of FDH, as well as a valuable tool to probe Wnt ligand function in vivo.