BackgroundThe Notch signaling pathway governs the specification of different cell types in flies, nematodes and vertebrates alike. Principal components of the pathway that activate Notch target genes are highly conserved throughout the animal kingdom. Despite the impact on development and disease, repression mechanisms are less well studied. Repressors are known from arthropods and vertebrates that differ strikingly by mode of action: whereas Drosophila Hairless assembles repressor complexes with CSL transcription factors, competition between activator and repressors occurs in vertebrates (for example SHARP/MINT and KyoT2). This divergence raises questions on the evolution: Are there common ancestors throughout the animal kingdom?ResultsAvailable genome databases representing all animal clades were searched for homologues of Hairless, SHARP and KyoT2. The most distant species with convincing Hairless orthologs belong to Myriapoda, indicating its emergence after the Mandibulata-Chelicarata radiation about 500 million years ago. SHARP shares motifs with SPEN and SPENITO proteins, present throughout the animal kingdom. The CSL interacting domain of SHARP, however, is specific to vertebrates separated by roughly 600 million years of evolution. KyoT2 bears a C-terminal CSL interaction domain (CID), present only in placental mammals but highly diverged already in marsupials, suggesting introduction roughly 100 million years ago. Based on the LIM-domains that characterize KyoT2, homologues can be found in Drosophila melanogaster (Limpet) and Hydra vulgaris (Prickle 3 like). These lack the CID of KyoT2, however, contain a PET and additional LIM domains. Conservation of intron/exon boundaries underscores the phylogenetic relationship between KyoT2, Limpet and Prickle. Most strikingly, Limpet and Prickle proteins carry a tetra-peptide motif resembling that of several CSL interactors. Overall, KyoT2 may have evolved from prickle and Limpet to a Notch repressor in mammals.ConclusionsNotch repressors appear to be specific to either chordates or arthropods. Orthologues of experimentally validated repressors were not found outside the phylogenetic group they have been originally identified. However, the data provide a hypothesis on the evolution of mammalian KyoT2 from Prickle like ancestors. The finding of a potential CSL interacting domain in Prickle homologues points to a novel, very ancestral CSL interactor present in the entire animal kingdom.

中文翻译：

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Notch信号通路中转录抑制因子的进化：计算分析

背景Notch信号通路控制果蝇、线虫和脊椎动物等不同细胞类型的规范。激活 Notch 靶基因的途径的主要成分在整个动物界都是高度保守的。尽管对发育和疾病有影响，但抑制机制的研究较少。阻遏物从节肢动物和脊椎动物中得知，它们的作用方式显着不同：而无毛果蝇将阻遏物与 CSL 转录因子组装在一起，而激活物和阻遏物之间的竞争发生在脊椎动物中（例如 SHARP/MINT 和 KyoT2）。这种分歧引发了关于进化的问题：整个动物王国是否有共同的祖先？结果搜索代表所有动物进化枝的可用基因组数据库寻找无毛的同源物，夏普和KyoT2。具有令人信服的无毛直系同源物的最遥远的物种属于多足纲，表明它是在大约 5 亿年前的下颌角-螯肢动物辐射之后出现的。SHARP 与 SPEN 和 SPENITO 蛋白共享基序，存在于整个动物界。然而，SHARP 的 CSL 相互作用域是特定于相隔大约 6 亿年进化的脊椎动物。KyoT2 具有 C 末端 CSL 相互作用域 (CID)，仅存在于胎盘哺乳动物中，但在有袋动物中已经高度分化，这表明大约 1 亿年前引入。基于表征 KyoT2 的 LIM 域，可以在黑腹果蝇 (Limpet) 和 Hydra vulgaris (Prickle 3 like) 中找到同源物。这些缺少 KyoT2 的 CID，但是，包含 PET 和其他 LIM 域。内含子/外显子边界的保守强调了 KyoT2、Limpet 和 Prickle 之间的系统发育关系。最引人注目的是，Limpet 和 Prickle 蛋白带有一个四肽基序，类似于几个 CSL 相互作用物。总体而言，KyoT2 可能已经从 prickle 和 Limpet 进化为哺乳动物中的 Notch 阻遏物。结论 Notch 阻遏物似乎对脊索动物或节肢动物具有特异性。在最初确定的系统发育组之外没有发现经过实验验证的阻遏物的直系同源物。然而，这些数据提供了一个关于哺乳动物 KyoT2 从 Prickle 类祖先进化而来的假设。在 Prickle 同源物中发现了一个潜在的 CSL 相互作用域，这表明整个动物界都存在一种新颖的、非常古老的 CSL 相互作用子。