Conservation of the Notch antagonist Hairless in arthropods: functional analysis of the crustacean Daphnia pulex Hairless gene

Zehender, Ariella; Bayer, Melanie; Bauer, Max; Zeis, Bettina; Preiss, Anette; Maier, Dieter

doi:10.1007/s00427-017-0593-4

Cited by 8 publications

(10 citation statements)

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“…Recently we identified Hairless orthologs outside of insects in two classes of crustacean, in Daphnia pulex (water flea, Branchiopoda) as well as in Litopenaeus vannamei (whiteleg shrimp, Malacostraca). Moreover, functional conservation of Daphnia pulex Hairless was confirmed experimentally in transgenic D. melanogaster [44]. Further searches identified Hairless orthologs in the crustacean Triops cancriformis (Tadpole shrimp) and potentially also in the centipede Strigamia maritima (European centipede).…”

Section: Resultsmentioning

confidence: 98%

“…Conservation of Hairless has been extensively studied (Fig. 1d): Orthologs are present in all insects studied to date as well as in some members of the subphylum Crustacea [9, 42–44]. The D. melanogaster Hairless protein consists of 1077/1059 residues, however, is significantly smaller in more distant species like the honeybee Apis mellifera (392 aa) or the water flea Daphnia pulex (448 aa).…”

Section: Introductionmentioning

confidence: 99%

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The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis

Maier

2019

Hereditas

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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.Electronic supplementary materialThe online version of this article (10.1186/s41065-019-0081-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis

Maier

2019

Hereditas

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“…For example, although SHARP, also known as SPEN in Drosophila and DIN-1 in C. elegans , is conserved from nematodes to flies to mammals ( Ariyoshi and Schwabe, 2003 ), the RBPID of SHARP is only conserved in vertebrates ( VanderWielen et al, 2011 ). Similarly, the corepressor Hairless, which is the major antagonist of Notch signaling in Drosophila , is not conserved outside of insects and crustaceans ( Zehender et al, 2017 ). However, although the corepressors that bind RBPJ are not strictly conserved across disparate organisms, interestingly, the corepressor binding sites on RBPJ are conserved.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site

et al. 2019

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SUMMARY Notch is a conserved signaling pathway that is essential for metazoan development and homeostasis; dysregulated signaling underlies the pathophysiology of numerous human diseases. Receptor-ligand interactions result in gene expression changes, which are regulated by the transcription factor RBPJ. RBPJ forms a complex with the intracellular domain of the Notch receptor and the coactivator Mastermind to activate transcription, but it can also function as a repressor by interacting with corepressor proteins. Here, we determine the structure of RBPJ bound to the corepressor SHARP and DNA, revealing its mode of binding to RBPJ. We tested structure-based mutants in biophysical and biochemical-cellular as-says to characterize the role of RBPJ as a repressor, clearly demonstrating that RBPJ mutants deficient for SHARP binding are incapable of repressing transcription of genes responsive to Notch signaling in cells. Altogether, our structure-function studies provide significant insights into the repressor function of RBPJ.

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“…For example, while SHARP, also known as SPEN in Drosophila and DIN-1 in C. elegans , is conserved from nematodes to flies to mammals 48 , the RBPID of SHARP is only conserved in vertebrates 27 . Similarly, the corepressor Hairless, which is the major antagonist of Notch signaling in Drosophila , is not conserved outside of insects and crustaceans 49 . However, while the corepressors that bind CSL are not strictly conserved across disparate organisms, interestingly, the corepressor binding sites on CSL are conserved.…”

Section: Discussionmentioning

confidence: 99%

Structural and functional studies of the RBPJ-SHARP complex reveal conserved corepressor binding site

Yuan

VanderWielen

Giaimo

et al. 2018

Preprint

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14The Notch pathway is a conserved signaling mechanism that is essential for cell fate decisions 15 during pre and postnatal development. Dysregulated signaling underlies the pathophysiology of 16 numerous human diseases, most notably T-cell acute lymphoblastic leukemia. Receptor-ligand 17 interactions result in changes in gene expression, which are regulated by the transcription factor 18 CSL. CSL forms a complex with the intracellular domain of the Notch receptor and the 19 transcriptional coactivator Mastermind, which is required to activate transcription of all Notch 20 target genes. CSL can also function as repressor by interacting with corepressor proteins, e.g. 21 SHARP in mammals and Hairless in Drosophila melanogaster; however, its role as a 22 transcriptional repressor is not well understood. Here we determine the high-resolution structure 23 of RBPJ, the mouse CSL ortholog, bound to the corepressor SHARP and DNA, which reveals a 24 new mode of corepressor binding to CSL and an interesting example for how ligand binding 25 sites evolve in proteins. Based on the structure, we designed and tested a number of mutants in 26 biophysical, biochemical, and cellular assays to characterize the role of RBPJ as a repressor of 27 Notch target genes. Our cellular studies clearly demonstrate that RBPJ mutants that are 28 deficient for binding SHARP are incapable of repressing transcription from genes responsive to 29 Notch signaling. Altogether, our structure-function studies of the RBPJ-SHARP corepressor 30 complex bound to DNA provide significant insights into the repressor function of RBPJ and 31 identify a new binding pocket on RBPJ that could be targeted for therapeutic benefit. 32 33

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Conservation of the Notch antagonist Hairless in arthropods: functional analysis of the crustacean Daphnia pulex Hairless gene

Cited by 8 publications

References 50 publications

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

Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site

Structural and functional studies of the RBPJ-SHARP complex reveal conserved corepressor binding site

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