Laboratoire de Biologie du Développement de Villefranche-sur-Mer (LBDV), Sorbonne Université, CNRS, Villefranche-sur-Mer, France.
Department of Cell and Developmental Biology, Silberman Life Sciences Institute, The Hebrew University of Jerusalem, Israel.
Genome Biol Evol. 2020 Feb 1;12(2):3957-3970. doi: 10.1093/gbe/evaa020.
Collagen triple helix repeat containing protein 1 (Cthrc1) is a secreted glycoprotein reported to regulate collagen deposition and to be linked to the Transforming growth factor β/Bone morphogenetic protein and the Wnt/planar cell polarity pathways. It was first identified as being induced upon injury to rat arteries and was found to be highly expressed in multiple human cancer types. Here, we explore the phylogenetic and evolutionary trends of this metazoan gene family, previously studied only in vertebrates. We identify Cthrc1 orthologs in two distant cnidarian species, the sea anemone Nematostella vectensis and the hydrozoan Clytia hemisphaerica, both of which harbor multiple copies of this gene. We find that Cthrc1 clade-specific diversification occurred multiple times in cnidarians as well as in most metazoan clades where we detected this gene. Many other groups, such as arthropods and nematodes, have entirely lost this gene family. Most vertebrates display a single highly conserved gene, and we show that the sequence evolutionary rate of Cthrc1 drastically decreased within the gnathostome lineage. Interestingly, this reduction coincided with the origin of its conserved upstream neighboring gene, Frizzled 6 (FZD6), which in mice has been shown to functionally interact with Cthrc1. Structural modeling methods further reveal that the yet uncharacterized C-terminal domain of Cthrc1 is similar in structure to the globular C1q superfamily domain, also found in the C-termini of collagens VIII and X. Thus, our studies show that the Cthrc1 genes are a collagen-like family with a variable short collagen triple helix domain and a highly conserved C-terminal domain structure resembling the C1q family.
胶原蛋白三螺旋重复蛋白 1（Cthrc1）是一种分泌性糖蛋白，据报道可调节胶原蛋白的沉积，并与转化生长因子 β/骨形态发生蛋白和 Wnt/平面细胞极性途径有关。它最初被鉴定为在大鼠动脉损伤时诱导产生的，并且在多种人类癌症类型中高度表达。在这里，我们探索了这个后生动物基因家族的系统发育和进化趋势，以前仅在脊椎动物中进行过研究。我们在两种遥远的刺胞动物物种中鉴定出 Cthrc1 直系同源物，海葵 Nematostella vectensis 和水螅 Clytia hemisphaerica，这两种物种都有多个这种基因的拷贝。我们发现，Cthrc1 分支特异性多样化在刺胞动物以及我们检测到这种基因的大多数后生动物类群中多次发生。许多其他群体，如节肢动物和线虫，完全失去了这个基因家族。大多数脊椎动物显示出一个单一的高度保守基因，我们表明 Cthrc1 的序列进化率在颌形动物谱系内急剧下降。有趣的是，这种减少与它保守的上游邻近基因 Frizzled 6（FZD6）的起源相吻合，在小鼠中已显示其与 Cthrc1 具有功能相互作用。结构建模方法进一步表明，Cthrc1 的尚未表征的 C 末端结构域在结构上与球状 C1q 超家族结构域相似，该结构域也存在于胶原蛋白 VIII 和 X 的 C 末端。因此，我们的研究表明，Cthrc1 基因是一个类似胶原蛋白的家族，具有可变的短胶原蛋白三螺旋结构域和高度保守的 C 末端结构域结构，类似于 C1q 家族。
