Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, Spain.
Growth and Development, University of Basel, Biozentrum, Switzerland.
Elife. 2021 Aug 6;10:e64581. doi: 10.7554/eLife.64581.
The conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication in development, tissue repair, and cancer progression, inducing distinct concentration-dependent responses in target cells located at short and long distances. One simple mechanism for long distance dispersal of the lipid modified Hh is the direct contact between cell membranes through filopodia-like structures known as cytonemes. Here we have analyzed in the interaction between the glypicans Dally and Dally-like protein, necessary for Hh signaling, and the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans are required to maintain the levels of Ihog, but not of Boi. We also show that the overexpression of Ihog, but not of Boi, regulates cytoneme dynamics through their interaction with glypicans, the Ihog fibronectin III domains being essential for this interaction. Our data suggest that the regulation of glypicans over Hh signaling is specifically given by their interaction with Ihog in cytonemes. Contrary to previous data, we also show that there is no redundancy of Ihog and Boi functions in Hh gradient formation, being Ihog, but not of Boi, essential for the long-range gradient.
Hedgehog (Hh) 信号蛋白家族在细胞间通讯中起着关键作用，在发育、组织修复和癌症进展中，诱导位于短距离和长距离的靶细胞产生不同的浓度依赖性反应。脂质修饰的 Hh 长距离扩散的一个简单机制是通过称为纤毛状结构的丝状伪足样结构在细胞膜之间的直接接触。在这里，我们分析了糖蛋白 Dally 和 Dally 样蛋白（Hh 信号所必需的）与黏附分子和 Hh 核心受体 Ihog 和 Boi 之间的相互作用。我们描述了糖蛋白对于维持 Ihog 的水平是必需的，但对于 Boi 则不是必需的。我们还表明，Ihog 的过表达，而不是 Boi 的过表达，通过与糖蛋白的相互作用来调节纤毛的动力学，Ihog 的纤连蛋白 III 结构域对于这种相互作用是必需的。我们的数据表明，糖蛋白对 Hh 信号的调节是由它们在纤毛中的与 Ihog 的相互作用特异性赋予的。与先前的数据相反，我们还表明，在 Hh 梯度形成中，Ihog 和 Boi 的功能没有冗余，Ihog 是必需的，而 Boi 则不是必需的。
