Temporal effects of Sprouty on lung morphogenesis

Perl, Anne‐Karina T.; Hokuto, Isamu; Impagnatiello, Maria-Antonietta; Christofori, Gerhard; Whitsett, Jeffrey A.

doi:10.1016/s0012-1606(03)00106-4

Cited by 62 publications

(40 citation statements)

References 28 publications

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“…In previous studies from our laboratory, the ability of the FGFR-HFc to inhibit effects of FGF-7 on lung branching was shown in vitro and in vivo (16). No effects of Sprouty-4 or FGFR-HFc receptors were observed in the postnatal period under physiological conditions (16,27). Although FGF ligands are present in the adult lung, it is unclear whether FGF signaling plays a role in postnatal lung homeostasis.…”

Section: Discussionmentioning

confidence: 93%

“…Targeted deletion of FGF-10, the FGFR2IIIb receptor, expression of a dominant-negative FGF receptor or Sprouty, an intracellular FGF antagonist, blocked lung morphogenesis during the early embryonic period (13,16,20,23,27). Although inhibition of FGF signaling until embryonic day 12 caused severe lung hypoplasia, the effects were less extensive when FGF inhibition was induced later in gestation.…”

Section: Discussionmentioning

confidence: 99%

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FGF signaling is required for pulmonary homeostasis following hyperoxia

Hokuto

Perl

Whitsett

2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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To assess the role of fibroblast growth factor (FGF) signaling in pulmonary function in the postnatal period, we generated transgenic mice in which a soluble FGF receptor (FGFR-HFc) was conditionally expressed in respiratory epithelial cells of the mouse lung, thereby inhibiting FGF activity. Although FGFR-HFc did not alter postnatal lung morphogenesis, male FGFR-HFc transgenic mice were more susceptible to hyperoxia and failed to recover when ambient oxygen concentrations were normalized. Inflammation, alveolar-capillary leak, and mortality were increased following exposure to 95% FI O 2 . Expression of surfactant protein (SP)-A and SP-B were significantly decreased in association with decreased immunostaining for thyroid transcription factor-1. FGF signaling is required for maintenance of surfactant homeostasis and lung function during hyperoxia in vivo, mediated, at least in part, by its role in the maintenance of SP-B expression. fibroblast growth factor; lung injury; surfactant protein; thyroid transcription factor-1 INHALED OXYGEN AND MECHANICAL ventilation remain the mainstay of respiratory therapy for acute respiratory distress. Despite the utility of oxygen in the maintenance of arterial oxygenation, oxygen is toxic, causing injury to both epithelial and vascular compartments of the lung. Exposure of adult mammals to 95-100% oxygen generally results in respiratory compromise and death within several days of continuous exposure (34). The lung responds to hyperoxia by enhancing the expression of cytoprotective proteins including antioxidants, surfactant proteins, and DNA repair enzymes (24,25,45). Although endotoxin, various cytokines, and polypeptide hormones, including IL-11, IL-6, EGF, and FGF-7 enhance cytoprotection of the lung during hyperoxia (4,5,30,37,(42)(43)(44), endogenous factors critical for survival and repair of the lung during oxygen exposure are not known.Intratracheal FGF-7 decreased lung injury and enhanced survival during acute lung injury caused by oxygen, acid instillation, and infection, presumably by interacting with FGF receptors on target cells. The protective effects of FGF required pretreatment of the animals before exposure to oxygen (26,46). It is less clear whether oxygen injury stimulates endogenous FGF receptor signaling to maintain pulmonary homeostasis during oxygen injury. In previous studies, transgenic mice were generated in which FGF receptor signaling was inhibited by expression of a dominant-negative soluble FGF receptor (FGFR-HFc) that was secreted by respiratory epithelial cells of the peripheral lung. Although expression of FGFR-HFc in epithelial cells of the embryonic lung blocked peripheral lung formation, its expression in the postnatal period did not alter lung morphogenesis or postnatal survival (16), thereby generating a model in which FGF signaling could be inhibited in the adult. To determine whether FGF signaling influences physiological processes in the postnatal lung, we assessed the effects of FGF receptor inhibition on pulmonary responses to hypero...

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

FGF signaling is required for pulmonary homeostasis following hyperoxia

Hokuto

Perl

Whitsett

2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The generation of transgenic FVB/N mice that conditionally express a soluble dominant-negative FGF receptor (FGFR-Hc) in the lung has been described elsewhere (18). Generation of transgenic mice conditionally expressing the FGF antagonist Sprouty-4 (Spry-4) in the developing lung epithelium has been described (19). Timed-pregnant females of both transgenic strains were given doxycycline in their food (625 mg/kg; Harlan-Teklad, Madison, WI) beginning on day E0.5, and embryonic lungs were harvested on day E13.5.…”

Section: Methodsmentioning

confidence: 99%

Erm/Thyroid Transcription Factor 1 Interactions Modulate Surfactant Protein C Transcription

Lin

Perl

Shannon

2006

Journal of Biological Chemistry

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Expression of surfactant protein C (SP-C), which is restricted to alveolar type II epithelial cells of the adult lung, is critically dependent on thyroid transcription factor 1 (TTF-1). In the present study we have demonstrated that Erm, a member of the Ets family of transcription factors, is expressed in the distal lung epithelium during development and is also restricted to alveolar type II cells in the adult. Erm was up-regulated by fibroblast growth factors (FGFs) in culture, and blocking FGF signaling inhibited Erm expression both in vivo and in vitro. The SP-C minimal promoter was found to contain two potential Ets binding sites, and electrophoretic mobility shift assays showed that two 20-bp wild-type oligonucleotides containing the 5-GGA(A/T)-3 Ets consensus binding motif were shifted by nuclear extracts from MLE15 cells. Co-transfection assays showed that Erm by itself had little effect on SP-C promoter activity but that Erm significantly enhanced TTF-1-mediated SP-C transcription. Mutation of one of the Ets binding sites reduced SP-C transcription to background levels, whereas mutation of the other site resulted in increased SP-C transcription. Protein-protein interactions between Erm and TTF-1 were demonstrated by mammalian two-hybrid assays and by co-immunoprecipitation assays. Mapping studies showed that the Ets domain of Erm and the combined N terminus and homeodomain of TTF-1 were critical for this interaction. Treatment of primary cultures of adult alveolar type II cells with siRNA targeting Erm diminished expression of both Erm and SP-C but had no effect on ␤-actin or GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Taken together, these results demonstrate that Erm is involved in SP-C regulation, which results from an interaction with TTF-1.Mouse lung development begins on embryonic day 9.5 (E9.5) 2 as two evaginations from the floor of the foregut endoderm into mesenchyme derived from splanchnic mesoderm. After a series of dichotomous and lateral branchings that form the pulmonary tree, the most distal epithelium continues to expand and mature during late gestation and early postnatal life to give rise to mature alveoli. Two cell types constitute the alveolar epithelium, alveolar type I and type II cells. Type I cells have a highly attenuated morphology that is ideally suited for gas exchange (1), whereas the more cuboidal type II cells function in a number of capacities. These include serving as progenitor cells for type I cells, directionally transporting sodium from apical to basolateral cell surfaces to minimize alveolar fluid, producing molecules involved in innate host defense, and synthesizing and secreting pulmonary surfactant (2).Proximate tissue interactions between the epithelium and mesenchyme play a critical role in lung morphogenesis and differentiation. Tissue recombination studies have shown that distal lung epithelial differentiation is induced as a specific response to signals produced by lung mesenchyme (3, 4). Furthermore, tissue recombination experiments in which epitheli...

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“…Mammalian Sprys have been shown to particularly function as negative regulators in FGF signaling during vertebrate embryonic development. The overexpression of mouse Spry2 or Spry4 results in the repression of FGF-mediated limb development in the chick (15) and inhibition of lung branching morphogenesis (14,18,19). In addition, the overexpression of mSpry4 in mouse embryos inhibited branching and sprouting of small blood vessels (20).…”

Section: Introductionmentioning

confidence: 99%

The Ras/Mitogen-Activated Protein Kinase Pathway Inhibitor and Likely Tumor Suppressor Proteins, Sprouty 1 and Sprouty 2 Are Deregulated in Breast Cancer

Lo¹,

Yusoff²,

Fong³

et al. 2004

Cancer Research

157

176

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Sprouty (Spry) proteins were found to be endogenous inhibitors of the Ras/mitogen-activated protein kinase pathway that play an important role in the remodeling of branching tissues. We investigated Spry expression levels in various cancers and found that Spry1 and Spry2 were downregulated consistently in breast cancers. Such prevalent patterns of downregulation may herald the later application of these isoforms as tumor markers that are breast cancer specific and more profound than currently characterized markers. Spry1 and 2 were expressed specifically in the luminal epithelial cells of breast ducts, with higher expression during stages of tissue remodeling when the epithelial ducts are forming and branching. These findings suggest that Sprys might be involved as a modeling counterbalance and surveillance against inappropriate epithelial expansion. The abrogation of endogenous Spry activity in MCF-7 cells by the overexpression of a previously characterized dominant-negative mutant of Spry, hSpry2Y55F resulted in enhanced cell proliferation in vitro. The hSpry2Y55F stably expressing cells also formed larger and greater number of colonies in the soft-agar assay. An in vivo nude mice assay showed a dramatic increase in the tumorigenic potential of hSpry2 Y55F stable cells. The consistent down-regulation of Spry1 and 2 in breast cancer and the experimental evidence using a dominant-negative hSpry2 Y55F indicate that Spry proteins may actively maintain tissue integrity that runs amok when their expression is decreased below normal threshold levels. This alludes to a previously unrecognized role for Sprys in cancer development.

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Temporal effects of Sprouty on lung morphogenesis

Cited by 62 publications

References 28 publications

FGF signaling is required for pulmonary homeostasis following hyperoxia

FGF signaling is required for pulmonary homeostasis following hyperoxia

Erm/Thyroid Transcription Factor 1 Interactions Modulate Surfactant Protein C Transcription

The Ras/Mitogen-Activated Protein Kinase Pathway Inhibitor and Likely Tumor Suppressor Proteins, Sprouty 1 and Sprouty 2 Are Deregulated in Breast Cancer

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