FGF receptors control alveolar elastogenesis [RESEARCH ARTICLE]

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

Alveologenesis is the final step of lung development characterized by the formation of millions of alveolar septa which constitute the vast gas-exchange surface area. The genetic network driving alveologenesis is poorly understood compared to those in earlier steps of lung development. Fibroblast Growth Factor (FGF) signaling through the FGF receptors, Fgfr3 and Fgfr4 (hereafter Fgfr3;4), is critical for alveologenesis. However, the mechanisms through which they mediate this process remain unclear. Here we show that in Fgfr3;4 global mutant mice, alveolar simplification is first observed at the onset of alveologenesis at postnatal day (P) 3. This is preceded by disorganization of Elastin, indicating defects in the extracellular matrix (ECM). While Fgfr3;4 are expressed in both the mesenchyme and the epithelium, inactivation in the mesenchyme, but not the epithelium recapitulated the defects. Expression analysis of components of the elastogenesis machinery revealed that the gene encoding Microfibrillar Associated Glycoprotein 2 (MAGP2, also known as MFAP5), an Elastin-Microfibril bridging factor, is upregulated in the Fgfr3;4 mutants. Introduction of Mfap5 mutation into the Fgfr3;4 mutant background partially attenuated the alveologenesis defects. Together these data demonstrate that during normal lung maturation, FGF signaling restricts the expression of the elastogenic machinery in the lung mesenchyme to control orderly formation of the Elastin extracellular matrix, thereby drive alveolar septa formation to increase the gas-exchange surface.

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