Tmem2 restricts atrioventricular canal differentiation by regulating degradation of hyaluronic acid.
Tmem2 restricts atrioventricular canal differentiation by regulating degradation of hyaluronic acid.
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DOI：
10.1002/dvdy.106
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Yelon D
中科院分区：
文献类型：
--
作者：
Hernandez L;Ryckebüsch L;Wang C;Ling R;Yelon D
房室瓣膜的发育依赖于房室管（AVC）精确定义的尺寸。目前的模型表明，Wnt信号在促进AVC发展的途径上起着重要作用。然而，限制AVC分化到适当位置的因素尚不清楚。跨膜蛋白2 （Tmem2）是限制AVC分化的关键因素：在斑马鱼中，Tmem2突变体表现出AVC特征的扩展，但在这种情况下Tmem2功能的分子机制尚不清楚。通过结构-功能分析，我们证明了Tmem2的细胞外部分对其限制AVC边界的作用至关重要。重要的是，Tmem2外结构域包含与透明质酸（HA）解聚有关的区域。我们发现tmem2突变心脏表现出过量的HA沉积以及Wnt信号的扩大分布。此外，添加异位透明质酸酶可以恢复tmem2突变体对AVC分化的限制。最后，我们发现在AVC发育过程中，HA解聚重要残基的改变会损害Tmem2功能的功效。综上所述，我们的数据支持一个模型，即由Tmem2调节的HA降解限制了Wnt信号的分布，从而限制了AVC的分化。
Atrioventricular valve development relies upon the precisely defined dimensions of the atrioventricular canal (AVC). Current models suggest that Wnt signaling plays an important role atop a pathway that promotes AVC development. The factors that confine AVC differentiation to the appropriate location, however, are less well understood. Transmembrane protein 2 (Tmem2) is a key player in restricting AVC differentiation: in zebrafish, tmem2 mutants display an expansion of AVC characteristics, but the molecular mechanism of Tmem2 function in this context remains unclear. Through structure-function analysis, we demonstrate that the extracellular portion of Tmem2 is crucial for its role in restricting AVC boundaries. Importantly, the Tmem2 ectodomain contains regions implicated in the depolymerization of hyaluronic acid (HA). We find that tmem2 mutant hearts exhibit excess HA deposition alongside broadened distribution of Wnt signaling. Moreover, addition of ectopic hyaluronidase can restore the restriction of AVC differentiation in tmem2 mutants. Finally, we show that alteration of a residue important for HA depolymerization impairs the efficacy of Tmem2 function during AVC development. Taken together, our data support a model in which HA degradation, regulated by Tmem2, limits the distribution of Wnt signaling and thereby confines the differentiation of the AVC.
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