Serpe Mihaela, Ralston Amy, Blair Seth S, O'Connor Michael B
Department of Genetics Cell Biology and Development, and the Developmental Biology Center, University of Minnesota and the Howard Hughes Medical Institute, Minneapolis, MN 55455, USA.
Development. 2005 Jun;132(11):2645-56. doi: 10.1242/dev.01838. Epub 2005 May 4.
The Drosophila tolloid (tld) and tolloid related (tlr) gene products belong to a family of developmentally important proteases that includes Bone Morphogenetic Protein 1 (Bmp1). Tld is required early in Drosophila development for proper patterning of dorsal embryonic structures, whereas Tlr is required later during larval and pupal stages of development. The major function of Tld is to augment the activity of Decapentaplegic (Dpp) and Screw (Scw), two members of the Bmp subgroup of the Tgf beta superfamily, by cleaving the Bmp inhibitor Short gastrulation (Sog). In this study, we provide evidence that Tlr also contributes to Sog processing. Tlr cleaves Sog in vitro in a Bmp-dependent manner at the same three major sites as does Tld. However, Tlr shows different site selection preferences and cleaves Sog with slower kinetics. To test whether these differences are important in vivo, we investigated the role of Tlr and Tld during development of the posterior crossvein (PCV) in the pupal wing. We show that tlr mutants lack the PCV as a result of too little Bmp signaling. This is probably caused by excess Sog activity, as the phenotype can be suppressed by lowering Sog levels. However, Tld cannot substitute for Tlr in the PCV; in fact, misexpressed Tld can cause loss of the PCV. Reducing levels of Sog can also cause loss of the PCV, indicating that Sog has not only an inhibitory but also a positive effect on signaling in the PCV. We propose that the specific catalytic properties of Tlr and Tld have evolved to achieve the proper balance between the inhibitory and positive activities of Sog in the PCV and early embryo, respectively. We further suggest that, as in the embryo, the positive effect of Sog upon Bmp signaling probably stems from its role in a ligand transport process.
果蝇类 tolloid（tld）和类 tolloid 相关（tlr）基因产物属于一类在发育过程中具有重要意义的蛋白酶家族，其中包括骨形态发生蛋白 1（Bmp1）。Tld 在果蝇发育早期对于胚胎背侧结构的正确模式形成是必需的，而 Tlr 在发育的幼虫和蛹期后期是必需的。Tld 的主要功能是通过切割 Bmp 抑制剂短胚轴（Sog）来增强转化生长因子β超家族 Bmp 亚组的两个成员，即骨形态发生蛋白 2（Dpp）和螺旋蛋白（Scw）的活性。在本研究中，我们提供证据表明 Tlr 也参与 Sog 的加工。Tlr 在体外以依赖 Bmp 的方式在与 Tld 相同的三个主要位点切割 Sog。然而，Tlr 表现出不同的位点选择偏好，并且以较慢的动力学切割 Sog。为了测试这些差异在体内是否重要，我们研究了 Tlr 和 Tld 在蛹翅后交叉脉（PCV）发育过程中的作用。我们表明，tlr 突变体由于 Bmp 信号过少而缺乏 PCV。这可能是由于 Sog 活性过高所致，因为降低 Sog 水平可以抑制该表型。然而，Tld 不能在 PCV 中替代 Tlr；事实上，错误表达的 Tld 会导致 PCV 缺失。降低 Sog 水平也会导致 PCV 缺失，这表明 Sog 不仅对 PCV 中的信号传导有抑制作用，而且有积极作用。我们提出，Tlr 和 Tld 的特定催化特性已经进化，以分别在 PCV 和早期胚胎中实现 Sog 的抑制和积极活性之间的适当平衡。我们进一步认为，与在胚胎中一样，Sog 对 Bmp 信号传导的积极作用可能源于其在配体运输过程中的作用。
