Tissue interaction mediated by neuregulin‐1 and ErbB receptors regulates epithelial morphogenesis of mouse embryonic submandibular gland

Miyazaki, Yukihiro; Nakanishi, Yasuo; Hieda, Yohki

doi:10.1002/dvdy.20078

Cited by 40 publications

(43 citation statements)

References 27 publications

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“…Interestingly, inhibition of EGFR or PI3K decreased Wnt4 , Wnt5b , Wnt7b and Wnt10a suggesting that Wnt expression is positively regulated by PI3K downstream of erbB signaling (Figure 4C). To investigate the erbB regulation of Wnt expression in the epithelium, isolated epithelia were treated with FGF10, and three erbB ligands that are involved in SMG epithelial development (Kera et al, 2014; Miyazaki et al, 2004). Addition of HBEGF, Tgfα or Nrg1 alone shows that that they rapidly increase Wnt4 , Wnt5b and Wnt10a expression within 4 h (Figure 4D).…”

Section: Resultsmentioning

confidence: 99%

Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors

et al. 2015

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Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance.

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Section: Resultsmentioning

confidence: 99%

Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors

et al. 2015

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“…The salivary epithelium thereby was proved to perform branching morphogenesis when embedded in a laminin-rich basementmembrane-like matrix and stimulated by epidermal growth factor (EGF; Nogawa and Takahashi, 1991). Since then, many studies have reported the involvement of EGF family ligands (transforming growth factor ␣, heparin-binding EGF, and neuregulin) and laminins in the branching morphogenesis of the salivary gland (Kadoya et al, 1995;Kashimata and Gresik, 1997;Hosokawa et al, 1999;Kashimata et al, 2000;Umeda et al, 2001;Koyama et al, 2003;Miyazaki et al, 2004;Kadoya and Yamashina, 2005). During the development of the mesenchyme-free culture of salivary epithelium, we introduced a serum-supplemented medium but paid little attention to the serum, because we had typically added serum as a source of nutrients for in vitro organ cultures.…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid cooperates with EGF in inducing branching morphogenesis of embryonic mouse salivary epithelium

Noguchi¹,

Okamoto²,

Kasama³

et al. 2005

Developmental Dynamics

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Epithelial morphogenesis is supported by diffusible growth factors and by nondiffusible cell substrata, such as laminin and fibronectin. When embedded in a laminin-rich basement-membrane substratum, embryonic mouse submandibular epithelium undergoes cell proliferation and branching morphogenesis in response to epidermal growth factor (EGF) in mesenchyme-free culture but not in serum-free medium. In this study, we sought to identify the biologically active factor in serum. As this factor was heat-stable and trypsinresistant, the lipid fraction was analyzed. Horse serum was fractionated by ethanol extraction, Folch partition with chloroform-methanol-water, and high-performance liquid chromatography, and we tested the branch-inducing activity of each fraction. We also analyzed the partially purified fraction with a mass spectrometer, indicating that the active fraction largely consisted of lysophosphatidyl-hexose. Finally we identified the molecule as lysophosphatidic acid (LPA), because, whereas lysophosphatidyl-inositol had only a slight branch-inducing activity, its relevant LPA fully substituted for serum and induced branching morphogenesis in cooperation with EGF. LPA receptor genes were expressed in submandibular epithelial cells. DNA-synthesizing cells were abundant only when cultured in the presence of both EGF and LPA, but not either singly. Developmental Dynamics 235:403-410, 2006.

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“…The expression of NRG1 in fibroblasts has been described by Wen et [48,49]. Another in vivo study focused on mesenchymederived NRG1 regulating the epithelial morphogenesis of mouse embryonic submandibular glands [50]. The activation of human monocyticlike THP-1 [THP1] (ATCCR TIB-202™) cells and peripheral blood monocytes was companied by up-regulation and secretion of NRG1, leading to paracrine activation of the erb receptors and contribution to the epithelial and connective tissue proliferation [51].…”

Section: Discussionmentioning

confidence: 99%

“…In the first step, we validated the efficiency of BMS777607 to inhibit Axl phosphorylation by treating Axloverexpressing NIH/3T3-Axl cells for 1 hour with serially diluted compound concentrations. Subsequently, we performed a phosphoAxl-specific ELISA and calculated the IC 50 values by applying a four-parameter logistic curve fit. BMS777607 inhibits Axl autophosphorylation at low nanomolar concentrations, displaying an IC 50 value of 0.006 μM as shown in Figure 2A.…”

Section: Inhibition Of the Axl Rtk Leads To Up-regulation Of Her3 Phomentioning

confidence: 99%

“…First, we determined the activity of these Axl TKIs in NIH/3T3 Axl-overexpressing cells. For this reason, we treated the cells for 1 hour with serially diluted compound concentrations of BMS777607, MPCD84111, and R428 and subsequently performed a phospho-Axl-specific ELISA to calculate the IC 50 values by applying a four-parameter logistic curve fit. As shown in Figure 1A, the compounds inhibited Axl phosphorylation at nanomolar concentrations, displaying IC 50 values for BMS777607 of 0.006 μM, MPCD84111 of 0.027 μM, and R428 of 0.043 μM.…”

Section: Her3 Induction Is a Common Feedback Mechanism Of Axl Inhibitorsmentioning

confidence: 99%

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801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

Torka¹,

Pénzes²,

Baumann³

et al. 2014

European Journal of Cancer

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The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies.

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Tissue interaction mediated by neuregulin‐1 and ErbB receptors regulates epithelial morphogenesis of mouse embryonic submandibular gland

Cited by 40 publications

References 27 publications

Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors

Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors

Lysophosphatidic acid cooperates with EGF in inducing branching morphogenesis of embryonic mouse salivary epithelium

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

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