Dickkopf-1 (DKK1) reveals that fibronectin is a major target of Wnt signaling in branching morphogenesis of the mouse embryonic lung

Langhe, Stijn P. De; Sala, F.G.; Moral, Pierre Del; Fairbanks, Timothy; Yamada, Katsushi; Warburton, David; Burns, R. Cartland; Bellusci, Savério

doi:10.1016/j.ydbio.2004.09.023

Cited by 200 publications

(216 citation statements)

References 51 publications

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“…For DKK-1 a role in regulation of fibronectin expression via inhibition of Wnt signaling was published (De Langhe et al, 2005). Here, we present a similar role for DKK-3.…”

Section: Discussionsupporting

confidence: 67%

Expression of Dickkopf genes is strongly reduced in malignant melanoma

et al. 2006

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The Dickkopf (DKK) genes were originally identified as factors inducing head formation in Xenopus. The genes code for inhibitors that are involved in Wnt signaling. We speculate that loss of DKK expression plays a role in development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for loss of DKK, especially DKK-3 transcription. We found that DKK-1, -2 and -3 were downregulated or lost in all cell lines and in most of the tumor samples analysed. Reduced DKK-3 expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction RT-PCR analysis. Functional assays with stable DKK-3 transfected cell lines revealed that DKK-3 expression increased cell-cell adhesion and decreased cell migration. Further, downregulation of fibronectin, snail-1 and re-expression of E-cadherin was found in the DKK-3 expressing cell clones supporting a role of DKK-3 in tumor progression. Our studies thus indicate that loss of DKK-3 expression may contribute to melanoma progression.

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“…For DKK-1 a role in regulation of fibronectin expression via inhibition of Wnt signaling was published (De Langhe et al, 2005). Here, we present a similar role for DKK-3.…”

Section: Discussionsupporting

confidence: 67%

Expression of Dickkopf genes is strongly reduced in malignant melanoma

et al. 2006

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“…In terms of the vasculature, DKK1 negatively regulates angiogenesis and neovascularization during lung development, in normal tissue repair, and in tumors. [57][58][59] Our results further define the importance of DKK1 in PAH by revealing that only in the presence of BMPR2 mutation did DKK1 treatment increase gene expression characteristic of the pro-remodeling lung MPCs, including increased expression of ACTA2 and matrix proteins. DKK1 also controls differentiation of adipocytes and influences metabolism via upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and inhibition of β-catenin.…”

Section: Discussionsupporting

confidence: 57%

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

et al. 2016

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Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that actively participates in disease processes, as well as the potential to translate these findings to vascular beds in other nonlung tissues, in this instance perivascular skin mesenchymal cells (MCs). We utilized posttransplant or autopsy lung explant-derived cells (ABCG2-expressing mesenchymal progenitor cells [MPCs], fibroblasts) and skin-derived MCs to test the hypothesis that perivascular ABCG2 MPCs derived from pulmonary arterial hypertension (PAH) patient lung and skin would express a gene profile reflective of ongoing vascular dysfunction. By analyzing the genetic signatures and pathways associated with abnormal ABCG2 lung MPC phenotypes during PAH and evaluating them in lung-and skinderived MCs, we have identified potential predictor genes for detection of PAH as well as a targetable mechanism to restore MPCs and microvascular function. These studies are the first to explore the utility of expanding the study of ABCG2 MPC regulation of the pulmonary microvasculature to the epidermis, in order to identify potential markers for adult lung vascular disease, such as PAH.Keywords: mesenchymal progenitor cells, skin, lung, microvascular, pulmonary hypertension, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, BMPR2, Wnt signaling, LRP6, DKK1. Pulmonary vascular dysfunction or disease (PVD) is characterized by altered lung vascular structure and function. A significant loss of vascular-bed function, as seen in PVD, is thought to precede the clinical presentation of pulmonary hypertension (PH). 1 PH is associated with a wide array of comorbid conditions, such as systemic sclerosis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, and also occurs as a primary PVD known as either idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH). 2-4 PH is characterized by elevated pulmonary artery pressures and widespread vascular remodeling, including endothelial cell dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. 5-7 All forms of PH have a high mortality rate despite current therapeutic options. The current limited understanding of PVD as a predecessor to PH and lack of diagnostic approaches or criteria specific to preclinical PVD have hampered the study of the early stages of PVD in both rodent models and the clinical setting.Approximately 80% of HPAH patients have a known mutation in the gene bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation-associated PAH is an autosomal dominant disease with low penetrance (approx. 20%); hence, not all mutation carriers develop PAH. In addition, approximately 20% of patients initially labeled as having IPAH also have a mutation in BMPR2 and thus heritable disease. 8 In addition to ge...

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“…In all cases we measured a significant decrease in the proportion of Caspase-3 positive cells among Krm1-transfected cells upon exposure to exogenous Dkk1 (Figures 3e-g). The fact that we never observed as good of a rescue using nonautonomous strategies as in cotransfection experiments could be due to the protein stability/ activity issues, as previously reported, 29 or to the existence of a pool of Krm1 that would remain inaccessible (intracellular for example) to exogenous ligand. From these experiments, we concluded that Krm1 is a bona fide dependence receptor whose apoptotic activity is inhibited upon ligand binding in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 57%

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

2015

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In multicellular organisms, a tight control of cell death is required to ensure normal development and tissue homeostasis. Improper function of apoptotic or survival pathways can not only affect developmental programs but also favor cancer progression. Here we describe a novel apoptotic signaling pathway involving the transmembrane receptor Kremen1 and its ligand, the Wnt-antagonist Dickkopf1. Using a whole embryo culture system, we first show that Dickkopf1 treatment promotes cell survival in a mouse model exhibiting increased apoptosis in the developing neural plate. Remarkably, this effect was not recapitulated by chemical Wnt inhibition. We then show that Dickkopf1 receptor Kremen1 is a bona fide dependence receptor, triggering cell death unless bound to its ligand. We performed Wnt-activity assays to demonstrate that the pro-apoptotic and anti-Wnt functions mediated by Kremen1 are strictly independent. Furthermore, we combined phylogenetic and mutagenesis approaches to identify a specific motif in the cytoplasmic tail of Kremen1, which is (i) specifically conserved in the lineage of placental mammals and (ii) strictly required for apoptosis induction. Finally, we show that somatic mutations of kremen1 found in human cancers can affect its pro-apoptotic activity, supporting a tumor suppressor function. Our findings thus reveal a new Wnt-independent function for Kremen1 and Dickkopf1 in the regulation of cell survival with potential implications in cancer therapies.

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Dickkopf-1 (DKK1) reveals that fibronectin is a major target of Wnt signaling in branching morphogenesis of the mouse embryonic lung

Cited by 200 publications

References 51 publications

Expression of Dickkopf genes is strongly reduced in malignant melanoma

Expression of Dickkopf genes is strongly reduced in malignant melanoma

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

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