Drosophila models of FOP provide mechanistic insight

Le, Victoria; Anderson, Ed; Akiyama, Takuya; Wharton, Kristi A.

doi:10.1016/j.bone.2017.11.001

Cited by 7 publications

(10 citation statements)

References 82 publications

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“…ALK2, which is widely expressed in mammalian cells, binds several TGFβ superfamily ligands, including Activins and TGFβ and may antagonise their signalling that proceeds via Smad2/3 phosphorylation 30–32. Thus, to determine if HLA-B27 would disturb TGFβ/BMP pathway signalling in SpA, we examined the phosphorylation of Smad2/3 in peripheral blood T lymphocytes from SpA patients (figure 6).…”

Section: Resultsmentioning

confidence: 99%

“…The mammalian orthologs of Sax are the BMPR1s ALK1 and ALK2, encoded by ACVRL1 and ACVR1 genes, respectively 32. ALK1 is predominantly present on endothelial cells and involved in angiogenesis, whereas ALK2 is more widely expressed and exerts an essential role in cartilage development and endochondral ossification, particularly in the axial skeleton 37 38.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to Sax, ALK1 and 2 play either a positive or a negative role in signalling, depending on the ligand and BMPR2 binding. They transduce signal in response to BMPs via Smad1/5/8 phosphorylation, whereas they antagonise signalling mediated by Activin and TGFβ via Smad2/3 phosphorylation or even BMP-mediated signalling in some circumstances 30–32 39 41–43. For instance, Activin A, is a ligand secreted by innate immune system cells during inflammation that primarily uses ALK4 and ALK7 as BMPR1s to initiate signalling via Smad2/3 39 44 45.…”

Section: Discussionmentioning

confidence: 99%

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HLA-B27 alters BMP/TGFβ signalling inDrosophila, revealing putative pathogenic mechanism for spondyloarthritis

et al. 2019

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ObjectivesThe human leucocyte antigen (HLA)-B27 confers an increased risk of spondyloarthritis (SpA) by unknown mechanism. The objective of this work was to uncover HLA-B27 non-canonical properties that could explain its pathogenicity, using a new Drosophila model.MethodsWe produced transgenic Drosophila expressing the SpA-associated HLA-B*27:04 or HLA-B*27:05 subtypes, or the non-associated HLA-B*07:02 allele, alone or in combination with human β2-microglobulin (hβ2m), under tissue-specific drivers. Consequences of transgenes expression in Drosophila were examined and affected pathways were investigated by the genetic interaction experiments. Predictions of the model were further tested in immune cells from patients with SpA.ResultsLoss of crossveins in the wings and a reduced eye phenotype were observed after expression of HLA-B*27:04 or HLA-B*27:05 in Drosophila but not in fruit flies expressing the non-associated HLA-B*07:02 allele. These HLA-B27-induced phenotypes required the presence of hβ2m that allowed expression of well-folded HLA-B conformers at the cell surface. Loss of crossveins resulted from a dominant negative effect of HLA-B27 on the type I bone morphogenetic protein (BMP) receptor saxophone (Sax) with which it interacted, resulting in elevated mothers against decapentaplegic (Mad, a Drosophila receptor-mediated Smad) phosphorylation. Likewise, in immune cells from patients with SpA, HLA-B27 specifically interacted with activin receptor-like kinase-2 (ALK2), the mammalian Sax ortholog, at the cell surface and elevated Smad phosphorylation was observed in response to activin A and transforming growth factor β (TGFβ).ConclusionsAntagonistic interaction of HLA-B27 with ALK2, which exerts inhibitory functions on the TGFβ/BMP signalling pathway at the cross-road between inflammation and ossification, could adequately explain SpA development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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HLA-B27 alters BMP/TGFβ signalling inDrosophila, revealing putative pathogenic mechanism for spondyloarthritis

et al. 2019

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“…Our genetic data suggest that Sax receptor activity is regulated by O-GlcNAc, and as Sax is a known target for phosphorylation by Ser/Thr kinases, we tested whether it is the direct target of Sxc in its modulation of epidermal Dpp/BMP signaling. To do this, we prepared lysates from wild-type and transgenic embryos (dorsal closure stage 8-12 hours after egg lay [AEL]) harboring a functionally-validated FLAG-tagged Sax isoform (Le et al, 2017). We extracted Sax-FLAG from transgenic embryo lysates by using ab13970 [AbCam], the antibody that recognizes FLAG.…”

Section: Sax Is Modified By O-glcnacmentioning

confidence: 99%

“…Years of additional molecular and genetic studies helped shape our mechanistic understanding of Sax as a type I BMP receptor Le et al, 2018;Wharton and Derynck, 2009). In the wing imaginal disc, Sax functions to transduce Gbb/BMP signaling directly in cooperation with Tkv (Haerry et al, 1998); and can also limit the availability of the Gbb ligand, thus acting as a Gbb/BMP signaling antagonist .…”

Section: The Sax Family Of Type I Bmp Receptorsmentioning

confidence: 99%

Regulation of BMP Signaling by O-GlcNAcylation

Moulton

Humphreys

et al. 2019

Preprint

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P P Mad P Tkv Put Dpp P P Mad P Mad P Tkv Put Dpp Put Dpp P P Sax Put Dpp P Sax O Sxc Normal glucose and Sxc Low glucose or no Sxc Extracellular space Cytoplasm Graphical Abstract Moulton et al. p. 2 Summary Precise regulation of signal transduction is critical throughout organismal life, both for embryonic development and for adult homeostasis. To ensure proper spatio-temporal signal transduction, Bone Morphogenetic Protein (BMP) signaling pathways, like all other signaling pathways, are regulated by both agonists and antagonists. Here, we report identification of a previously unrecognized method of signal antagonism for Dpp (Decapentaplegic), a Drosophila BMP family member. We demonstrate that the BMP type I receptor Saxophone (Sax) functions as a Dpp receptor in the Drosophila embryonic epidermis, but that its activity is normally inhibited by the Olinked glycosyltransferase Super sex combs (Sxc). In wild-type embryos, inhibition of Saxophone (Sax) activity in the epidermis marks the BMP type I receptor Thickveins (Tkv) as the sole conduit for Dpp. In contrast, in sxc mutants, the Dpp signal is transduced by both Tkv and Sax, and elevated Dpp signaling induces errors in embryonic development that lead to embryonic death.We also demonstrate that Sax is the O-glycosylated target of Sxc and that O-glycosylation of Sax can be modulated by dietary sugar. Together, these findings link fertility to nutritive environment and point to Sax (activin receptor-like kinase [Alk] 1/2) signaling as the nutrient-sensitive branch of BMP signaling.

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