The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis
The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis
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DOI：
10.1186/s41065-019-0081-0
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发表时间：
2019-01-17
期刊：
影响因子：
2.7
通讯作者：
Maier, Dieter
中科院分区：
文献类型：
--
作者：
Maier, Dieter
背景：Notch信号通路控制着苍蝇、线虫和脊椎动物中不同细胞类型的特性。激活Notch靶基因的途径的主要成分在整个动物界都高度保守。尽管对发育和疾病有影响，但对抑制机制的研究较少。抑制因子与节肢动物和脊椎动物在作用方式上存在显著差异：无毛果蝇与CSL转录因子组装抑制因子复合体，而脊椎动物(例如Sharp/Mint和KyoT2)则存在激活因子和抑制因子之间的竞争。这种分歧引发了关于进化的问题：整个动物界有共同的祖先吗？结果：搜索了现有的代表所有动物支系的基因组数据库，寻找了无毛、夏普和KyoT2的同源物。拥有令人信服的无毛直系物的最遥远的物种属于多足类动物，这表明它是在大约5亿年前的Mandibuata-Chericarata辐射之后出现的。夏普与SPEN和SPENITO蛋白有相同的基序，存在于动物界。然而，夏普的CSL相互作用区域是特定于脊椎动物的，它们之间的进化间隔大约为6亿年。KyoT2带有一个C端的CSL相互作用域(CID)，该结构域只存在于胎盘哺乳动物中，但在有袋类动物中已经高度分化，这表明大约在1亿年前就引入了KyoT2。基于KyoT2的LIM结构域，可以在果蝇(Limtet)和普通九头蛇(Hdra Common Garis)(类刺3)中找到同源物。这些缺乏KyoT2的CID，然而，包含一个PET和额外的LIM结构域。内含子/外显子边界的保守性强调了KyoT2、Limet和Pickle之间的系统发育关系。最引人注目的是，Limet和Pickle蛋白携带一个四肽基序，类似于几个CSL相互作用元件。总体而言，在哺乳动物中，KyoT2可能已经从棘突和帽状突起进化为缺口抑制因子。在最初确定的系统发育组之外，没有发现经过实验验证的抑制子的同源基因。然而，这些数据为哺乳动物KyoT2从带刺的祖先进化提供了一个假说。在皮刺同源物中发现一个潜在的CSL相互作用结构域，这表明整个动物界存在一种新颖的、非常祖传的CSL相互作用元件。
Background: The 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?Results: Available 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.Conclusions: Notch 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.