Emilin3 is required for notochord sheath integrity and interacts with Scube2 to regulate notochord-derived Hedgehog signals

Corallo, Diana; Schiavinato, Alvise; Trapani, Valeria; Moro, Enrico; Argenton, Francesco; Bonaldo, Paolo

doi:10.1242/dev.094078

Cited by 39 publications

(47 citation statements)

References 42 publications

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“…To obtain the vector carrying Bmp-responsive elements, a transcription cassette (−1046;−863) with the minimal promoter region and the TATA box of the human ID1 gene was isolated from the plasmid pID183 (López-Rovira et al, 2002). The Shh-responsive construct is described elsewhere (Corallo et al, 2013). Each p5EMCS containing the responsive elements was recombined with middle pME-MCS vectors carrying the fluorescent protein coding sequences (GFP/mCherry).…”

Section: Methodsmentioning

confidence: 99%

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Schiavone

Rampazzo

Casari

et al. 2014

Disease Models &Amp; Mechanisms

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Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRASG12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRASG12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRASG12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRASG12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRASG12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.

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Section: Methodsmentioning

confidence: 99%

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Schiavone

Rampazzo

Casari

et al. 2014

Disease Models &Amp; Mechanisms

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“…This group includes MULTIMERIN1 [217], MULTIMERIN2 [218], EMILIN1 [219], and EMILIN2 [220]. The second group comprises only one molecule, EMILIN3 which lacks the gC1q domain and is required for notochord formation [221,222]. …”

Section: The Eden Family: Two Members With Opposite Functionsmentioning

confidence: 99%

Extracellular Matrix, a Hard Player in Angiogenesis

Mongiat

Andreuzzi

Tarticchio

et al. 2016

IJMS

174

133

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The extracellular matrix (ECM) is a complex network of proteins, glycoproteins, proteoglycans, and polysaccharides. Through multiple interactions with each other and the cell surface receptors, not only the ECM determines the physical and mechanical properties of the tissues, but also profoundly influences cell behavior and many physiological and pathological processes. One of the functions that have been extensively explored is its impingement on angiogenesis. The strong impact of the ECM in this context is both direct and indirect by virtue of its ability to interact and/or store several growth factors and cytokines. The aim of this review is to provide some examples of the complex molecular mechanisms that are elicited by these molecules in promoting or weakening the angiogenic processes. The scenario is intricate, since matrix remodeling often generates fragments displaying opposite effects compared to those exerted by the whole molecules. Thus, the balance will tilt towards angiogenesis or angiostasis depending on the relative expression of pro- or anti-angiogenetic molecules/fragments composing the matrix of a given tissue. One of the vital aspects of this field of research is that, for its endogenous nature, the ECM can be viewed as a reservoir to draw from for the development of new more efficacious therapies to treat angiogenesis-dependent pathologies.

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“…This finding allows to speculate that EMILIN-2 produced by MC3T3-E1 cells may serve as extracellular modulator of osteoblast maturation. EMILIN-2 directly interacts with Wnt1 8 , belonging to Wnt family members which were shown to be expressed in calvarial tissue and osteoblast cultures 37 . Since Wnt signaling is known to regulate osteoblastogenesis and therefore bone mass 38 , it may be plausible that EMILIN-2 produced by osteoblasts has a regulatory function in the maturation process of osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…EMILINs were found to influence pro-TGF-β processing 5, 6 , modulate Wnt and Hedgehog signaling 7, 8 , activate death receptor mediated apoptosis 9 , and communicate with cells via α4β1 and α9β1 integrin mediated signalling 3 . Despite these unique functions in the regulation of cell fate, little is known about a potential role of EMILINs in the organization of the extracellular matrix (ECM) and therefore their contribution to specialized extracellular supramolecular networks in different tissues.…”

Section: Introductionmentioning

confidence: 99%

Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts

Schiavinato

Keene

Imhof

et al. 2017

Sci Rep

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Tissue microenvironments formed by extracellular matrix networks play an important role in regulating tissue structure and function. Extracellular microfibrillar networks composed of fibrillins and their associated ligands such as LTBPs, fibulins, and EMILINs are of particular interest in this regard since they provide a specialized cellular microenvironment guiding proper morphology and functional behavior of specialized cell types. To understand how cellular microenvironments composed of intricate microfibrillar networks influence cell fate decisions in a contextual manner, more information about the spatiotemporal localization, deposition, and function of their components is required. By employing confocal immunofluorescence and electron microscopy we investigated the localization and extracellular matrix deposition of EMILIN-1 and -2 in tissues of the skeletal system such as cartilage and bone as well as in in vitro cultures of osteoblasts. We found that upon RNAi mediated depletion of EMILIN-1 in primary calvarial osteoblasts and MC3T3-E1 cells only fibulin-4 matrix deposition was lost while other fibulin family members or LTBPs remained unaffected. Immunoprecipitation and ELISA-style binding assays confirmed a direct interaction between EMILIN-1 and fibulin-4. Our data suggest a new function for EMILIN-1 which implies the guidance of linear fibulin-4 matrix deposition and thereby fibulin-4 fiber formation.

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Emilin3 is required for notochord sheath integrity and interacts with Scube2 to regulate notochord-derived Hedgehog signals

Cited by 39 publications

References 42 publications

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Extracellular Matrix, a Hard Player in Angiogenesis

Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts

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