FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching

Yin, Yongjun; Ornitz, David M.

doi:10.1126/scisignal.aay4353

Cited by 43 publications

(52 citation statements)

References 77 publications

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“…FGFs and FGFRs would alter in cancer cells associated with receptor overexpression and/or the aberrant FGFs secretion [ 61 ]. FGF9 has been reported to exhibit the high affinity with FGFR2 and FGFR3, and the low affinity to FGFR1 and FGFR4 [ 63 , 64 , 65 , 66 ]. In our observations, FGF9 stimulated the expression of FGFR1-4 in MA-10 tumor cells in vitro and in vivo [ 31 ] ( Figure 6 and Figure 8 ).…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effect of Cordycepin on FGF9-Induced Testicular Tumorigenesis

Chang

Hong

Yang

et al. 2020

IJMS

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Cordycepin, a bioactive constituent from the fungus Cordyceps sinensis, could inhibit cancer cell proliferation and promote cell death via induction of cell cycle arrest, apoptosis and autophagy. Our novel finding from microarray analysis of cordycepin-treated MA-10 mouse Leydig tumor cells is that cordycepin down-regulated the mRNA levels of FGF9, FGF18, FGFR2 and FGFR3 genes in MA-10 cells. Meanwhile, the IPA-MAP pathway prediction result showed that cordycepin inhibited MA-10 cell proliferation by suppressing FGFs/FGFRs pathways. The in vitro study further revealed that cordycepin decreased FGF9-induced MA-10 cell proliferation by inhibiting the expressions of p-ERK1/2, p-Rb and E2F1, and subsequently reducing the expressions of cyclins and CDKs. In addition, a mouse allograft model was performed by intratumoral injection of FGF9 and/or intraperitoneal injection of cordycepin to MA-10-tumor bearing C57BL/6J mice. Results showed that FGF9-induced tumor growth in cordycepin-treated mice was significantly smaller than that in a PBS-treated control group. Furthermore, cordycepin decreased FGF9-induced FGFR1-4 protein expressions in vitro and in vivo. In summary, cordycepin inhibited FGF9-induced testicular tumor growth by suppressing the ERK1/2, Rb/E2F1, cell cycle pathways, and the expressions of FGFR1-4 proteins, suggesting that cordycepin can be used as a novel anticancer drug for testicular cancers.

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Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effect of Cordycepin on FGF9-Induced Testicular Tumorigenesis

Chang

Hong

Yang

et al. 2020

IJMS

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“…ERK1/2 has been shown to relay signaling from FGF receptors in early fish, frog, chick and mouse embryos ( Christen and Slack, 1999 ; Corson et al, 2003 ; Lunn et al, 2007 ). In the lung, mesenchymal Fgf10 signals to the epithelium through Fgfr2b to promote proliferation and differentiation by activating the MAP kinase signaling pathway ( Yin and Ornitz, 2020 ). MAPK signaling consists of a series of phosphorylation cascades involving 3 kinases, RAF, MEK 1/2 and MAP (ERK1/2) kinases.…”

Section: Introductionmentioning

confidence: 99%

An Essential Requirement for Fgf10 in Pinna Extension Sheds Light on Auricle Defects in LADD Syndrome

Yang

Fons

Hajihosseini

et al. 2020

Front. Cell Dev. Biol.

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The pinna (or auricle) is part of the external ear, acting to capture and funnel sound toward the middle ear. The pinna is defective in a number of craniofacial syndromes, including Lacrimo-auriculo-dento-digital (LADD) syndrome, which is caused by mutations in FGF10 or its receptor FGFR2b. Here we study pinna defects in the Fgf10 knockout mouse. We show that Fgf10 is expressed in both the muscles and forming cartilage of the developing external ear, with loss of signaling leading to a failure in the normal extension of the pinna over the ear canal. Conditional knockout of Fgf10 in the neural crest fails to recapitulate this phenotype, suggesting that the defect is due to loss of Fgf10 from the muscles, or that this source of Fgf10 can compensate for loss in the forming cartilage. The defect in the Fgf10 null mouse is driven by a reduction in proliferation, rather than an increase in cell death, which can be partially phenocopied by inhibiting cell proliferation in explant culture. Overall, we highlight the mechanisms that could lead to the phenotype observed in LADD syndrome patients and potentially explain the formation of similar low-set and cup shaped ears observed in other syndromes.

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“…In addition to IGF1R, a number of RTKs, e.g., PDGFRα and FGFR3-4, are expressed in subsets of lung mesenchymal cells and are known to play roles in the regulation of myofibroblast activity. Activation of PDGFα and FGFR signaling is known to regulate elastogenesis ( 10 , 17 ) and both activate cellular processes via PI3K/AKT ( 55 , 56 ). Recent findings that Vangl2 regulates AKT activity during alveologenesis and is activated by noncanonical Wnt signaling support the concept that myofibroblast activity is mediated through the orchestration of IGF1R and other RTK signaling and the noncanonical Wnt/PCP pathways ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis

He¹,

Snowball²,

Sun³

et al. 2021

JCI Insight

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Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene ( Igf1r ) expression by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC, and nuclear YAP in myofibroblasts was dependent on Igf1r . Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation, and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.

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FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching

Cited by 43 publications

References 77 publications

Anti-Cancer Effect of Cordycepin on FGF9-Induced Testicular Tumorigenesis

Anti-Cancer Effect of Cordycepin on FGF9-Induced Testicular Tumorigenesis

An Essential Requirement for Fgf10 in Pinna Extension Sheds Light on Auricle Defects in LADD Syndrome

IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis

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