Simulations demonstrate a simple network to be sufficient to control branch point selection, smooth muscle and vasculature formation during lung branching morphogenesis

TL;DR

This study uses simulations to show that a simple network involving FGF9, FGF10, SHH, and Ptc can effectively model lung branching, smooth muscle development, and vasculature formation, aligning with experimental observations.

Contribution

The paper demonstrates that adding FGF9 to a known signaling network suffices to predict lung morphogenesis and associated tissue developments, simplifying previous complex models.

Findings

A minimal network reproduces lung branching patterns.

Model predicts smooth muscle formation in lung clefts.

Model aligns with mutant and culture experiment results.

Abstract

Proper lung functioning requires not only a correct structure of the conducting airway tree, but also the simultaneous development of smooth muscles and vasculature. Lung branching morphogenesis is strongly stereotyped and involves the recursive use of only three modes of branching. We have previously shown that the experimentally described interactions between Fibroblast growth factor (FGF)10, Sonic hedgehog (SHH) and Patched (Ptc) can give rise to a Turing mechanism that not only reproduces the experimentally observed wildtype branching pattern but also, in part counterintuitive, patterns in mutant mice. Here we show that, even though many proteins affect smooth muscle formation and the expression of Vegfa, an inducer of blood vessel formation, it is sufficient to add FGF9 to the FGF10/SHH/Ptc module to successfully predict simultaneously the emergence of smooth muscles in the clefts between growing lung buds, and Vegfa expression in the distal sub-epithelial mesenchyme. Our model reproduces the phenotype of both wildtype and relevant mutant mice, as well as the results of most culture conditions described in the literature.