FGF receptors control alveolar elastogenesis

Development. 2017 Dec 15;144(24):4563-4572. doi: 10.1242/dev.149443. Epub 2017 Nov 9.

Abstract

Alveologenesis, the final step of lung development, is characterized by the formation of millions of alveolar septa that constitute the vast gas-exchange surface area. The genetic network driving alveologenesis is poorly understood compared with earlier steps in lung development. FGF signaling through receptors Fgfr3 and Fgfr4 is crucial for alveologenesis, but the mechanisms through which they mediate this process remain unclear. Here we show that in Fgfr3;Fgfr4 (Fgfr3;4) global mutant mice, alveolar simplification is first observed at the onset of alveologenesis at postnatal day 3. This is preceded by disorganization of elastin, indicating defects in the extracellular matrix (ECM). Although Fgfr3 and Fgfr4 are expressed in the mesenchyme and epithelium, inactivation in the mesenchyme, but not the epithelium, recapitulated the defects. Expression analysis of components of the elastogenesis machinery revealed that Mfap5 (also known as Magp2), which encodes an elastin-microfibril bridging factor, is upregulated in Fgfr3;4 mutants. Mfap5 mutation in the Fgfr3;4 mutant background partially attenuated the alveologenesis defects. These data demonstrate that, during normal lung maturation, FGF signaling restricts expression of the elastogenic machinery in the lung mesenchyme to control orderly formation of the elastin ECM, thereby driving alveolar septa formation to increase the gas-exchange surface.

Keywords: Alveologenesis; Elastin extracellular matrix; FGF signaling; Lung development; Mouse.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Contractile Proteins / biosynthesis*
  • Contractile Proteins / genetics
  • Epithelium / metabolism
  • Extracellular Matrix / pathology
  • Extracellular Matrix Proteins / biosynthesis*
  • Extracellular Matrix Proteins / genetics
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Organogenesis / physiology*
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / embryology*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism*
  • Signal Transduction / physiology

Substances

  • Contractile Proteins
  • Extracellular Matrix Proteins
  • microfibrillar protein
  • Fgfr3 protein, mouse
  • Fgfr4 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, Fibroblast Growth Factor, Type 4