FGF receptors control alveolar elastogenesis

Li, Rongbo; Herriges, John; Chen, Lin; Mecham, Robert P.; Sun, Xin

doi:10.1242/dev.149443

Cited by 32 publications

(36 citation statements)

References 59 publications

(84 reference statements)

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“…In addition, since the Tbx4rtTA;TetOCre allele exclusively deletes in the lung mesenchyme, our data provide strong support that the mesodermally derived lung fibroblasts are the primary drivers of elastogenesis during early postnatal stages. The precise organization of the alveolar ECM is essential for proper alveolar development (40)(41)(42)(43)(44)(45). Our data show no differences in the formation of any of the alveolar ECM components in conditional Hox5 mutants except for disruption of the elastin matrix.…”

Section: Discussionmentioning

confidence: 57%

“…The Elastin-Based ECM Network Is Severely Disrupted in Hox5 Triple-Mutant Distal Lungs. Previous studies have shown that the ECM plays a fundamental role in coordinating proper alveologenesis in the distal lung (40)(41)(42)(43)(44)(45). We, therefore, analyzed several key ECM components in conditional P0-P7 Dox-treated Hox5 triplemutant mice and compared them with controls.…”

Section: Hox5 Genes Exhibit Highest Levels Of Expression During Earlymentioning

confidence: 99%

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Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Hrycaj

Marty-Santos

Cebrián

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Hox5genes (Hoxa5,Hoxb5,Hoxc5) are exclusively expressed in the lung mesenchyme during embryogenesis, and the most severe phenotypes result from constitutive loss of function of all three genes. BecauseHox5triple null mutants exhibit perinatal lethality, the contribution of this paralogous group to postembryonic lung development is unknown. Intriguingly, expression of all threeHox5genes peaks during the first 2 weeks after birth, reaching levels far exceeding those measured at embryonic stages, and survivingHoxa5single andHox5 AabbCccompound mutants exhibit defects in the localization of alveolar myofibroblasts. To define the contribution of the entireHox5paralogous group to this process, we generated anHoxa5conditional allele to use with our existing null alleles forHoxb5andHoxc5. Postnatally, mesenchymal deletion ofHoxa5in anHoxb5/Hoxc5double-mutant background results in severe alveolar simplification. The elastin network required for alveolar formation is dramatically disrupted inHox5triple mutants, while the basal lamina, interstitial matrix, and fibronectin are normal. Alveolar myofibroblasts remain Pdgfrα+/SMA+ double positive and present in normal numbers, indicating that the irregular elastin network is not due to fibroblast differentiation defects. Rather, we observe that SMA+ myofibroblasts ofHox5triple mutants are morphologically abnormal both in vivo and in vitro with highly reduced adherence to fibronectin. This loss of adhesion is a result of loss of the integrin heterodimer Itga5b1 in mutant fibroblasts. Collectively, these data show an important role forHox5genes in lung fibroblast adhesion necessary for proper elastin network formation during alveologenesis.

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Section: Discussionmentioning

confidence: 57%

Section: Hox5 Genes Exhibit Highest Levels Of Expression During Earlymentioning

confidence: 99%

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Hrycaj

Marty-Santos

Cebrián

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Elastogenesis is a complex and highly regulated process (Sproul and Argraves, 2013). Disrupted elastogenesis leads to abnormal alveologenesis (Wendel et al, 2000;McGowan and McCoy, 2014;Li et al, 2017). In the lung, the mechanisms that functionally link PDGFRα and elastogenic genes had remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis

Lee

Gao

et al. 2019

Development

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Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGFβ signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/ PDGFRα in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGFβ.

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“…Several FGF ligands and all four Fgf receptors (Fgfr1–4), alongside splice variants, have been reported in the developing rodent lung . Studies in mice have shown that perturbation of one or more FGF ligands and/or receptors, particularly Fgf9 and Fgf10, can lead to branching defects.…”

Section: Introductionmentioning

confidence: 99%

Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse

Danopoulos

Thornton

Grubbs

et al. 2018

The Journal of Pathology

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Fibroblast growth factor (FGF) signaling plays an important role in lung organogenesis. Over recent decades, FGF signaling in lung development has been extensively studied in animal models. However, little is known about the expression, localization, and functional roles of FGF ligands during human fetal lung development. Therefore, we aimed to determine the expression and function of several FGF ligands and receptors in human lung development. Using in situ hybridization (ISH) and RNA sequencing, we assessed their expression and distribution in native human fetal lung. Human fetal lung explants were treated with recombinant FGF7, FGF9, or FGF10 in air–liquid interface culture. Explants were analyzed grossly to observe differences in branching pattern as well as at the cellular and molecular level. ISH demonstrated that FGF7 is expressed in both the epithelium and mesenchyme; FGF9 is mainly localized in the distal epithelium, whereas FGF10 demonstrated diffuse expression throughout the parenchyma, with some expression in the smooth muscle cells (SMCs). FGFR2 expression was high in both proximal and distal epithelial cells as well as the SMCs. FGFR3 was expressed mostly in the epithelial cells, with lower expression in the mesenchyme, while FGFR4 was highly expressed throughout the mesenchyme and in the distal epithelium. Using recombinant FGFs, we demonstrated that FGF7 and FGF9 had similar effects on human fetal lung as on mouse fetal lung; however, FGF10 caused the human explants to expand and form cysts as opposed to inducing epithelial branching as seen in the mouse. In conjunction with decreased branching, treatment with recombinant FGF7, FGF9, and FGF10 also resulted in decreased double‐positive SOX2/SOX9 progenitor cells, which are exclusively present in the distal epithelial tips in early human fetal lung. Although FGF ligand localization may be somewhat comparable between developing mouse and human lungs, their functional roles may differ substantially. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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FGF receptors control alveolar elastogenesis

Cited by 32 publications

References 59 publications

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Hox5genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion

Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis

Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse

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