Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Department of Molecular and Cell Biology, University of California-Berkeley, 571 Weill Hall, Berkeley, CA 94702.
Mol Biol Evol. 2023 Feb 3;40(2). doi: 10.1093/molbev/msac270.
Asymmetries are essential for proper organization and function of organ systems. Genetic studies in bilaterians have shown signaling through the Nodal/Smad2 pathway plays a key, conserved role in the establishment of body asymmetries. Although the main molecular players in the network for the establishment of left-right asymmetry (LRA) have been deeply described in deuterostomes, little is known about the regulation of Nodal signaling in spiralians. Here, we identified orthologs of the egf-cfc gene, a master regulator of the Nodal pathway in vertebrates, in several invertebrate species, which includes the first evidence of its presence in non-deuterostomes. Our functional experiments indicate that despite being present, egf-cfc does not play a role in the establishment of LRA in gastropods. However, experiments in zebrafish suggest that a single amino acid mutation in the egf-cfc gene in at least the common ancestor of chordates was the necessary step to induce a gain of function in LRA regulation. This study shows that the egf-cfc gene likely appeared in the ancestors of deuterostomes and "protostomes", before being adopted as a mechanism to regulate the Nodal pathway and the establishment of LRA in some lineages of deuterostomes.
不对称性对于器官系统的正常组织和功能至关重要。两侧对称动物的遗传研究表明，通过 Nodal/Smad2 信号通路进行信号传递，在建立身体不对称性方面发挥着关键的、保守的作用。尽管在后口动物中已经深入描述了建立左右不对称性（LRA）的网络中的主要分子参与者，但关于螺旋动物中 Nodal 信号的调节知之甚少。在这里，我们在几种无脊椎动物物种中鉴定出了 egf-cfc 基因的同源物，该基因是脊椎动物 Nodal 通路的主要调节因子，这是首次在非后口动物中发现该基因。我们的功能实验表明，尽管 egf-cfc 存在，但它在腹足动物 LRA 的建立中不起作用。然而，斑马鱼实验表明，至少在脊索动物的共同祖先中，egf-cfc 基因中的一个单一氨基酸突变是诱导 LRA 调节功能获得所必需的步骤。本研究表明，egf-cfc 基因可能出现在后口动物和“原口动物”的祖先中，然后被用作调节 Nodal 通路和一些后口动物谱系中 LRA 建立的机制。
