Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a provisional response from the authors.
Read more about eLife’s peer review process.Editors
- Reviewing EditorAnurag AgrawalAshoka University, Sonepat, India
- Senior EditorSofia AraújoUniversity of Barcelona, Barcelona, Spain
Reviewer #1 (Public review):
Summary:
This is an important contribution to the field of molecular embryology of the lung. The authors introduce a novel mesenchymally expressed molecule Svep1. Knocking it out in mice produces a profoundly hypoplastic phenotype which can be rescued in vitro. Svep1 interacts with the FGF signaling complex to control differentiation and expression of smooth muscle in lung mesenchyme, thereby affecting proximal-distal patterning of the airway branches by acting as a putative branch suppressor.
Strengths:
The study shows strong evidence in mouse knockouts, in vitro embryonic lung culture as well as gene expression and in vitro rescue studies that confirm a key role for Svep1. It is a beautiful piece of work and an important contribution to our understanding of early lung branching morphogenesis.
Weaknesses:
Claiming a possible therapeutic role for this gene is a bit far-fetched at the present state of the art.
Reviewer #2 (Public review):
Summary:
In an effort to elucidate the role of the ECM protein Svep1 in lung development, Foxworth and colleagues have generated a Svep1 mutant (lacking exon 8). Based on their developmental analyses of branching morphogenesis and expression of epithelial, mesenchymal, and mesothelial markers in these mutants, the authors conclude that Svep1 is essential for normal lung growth, morphogenesis, and patterning. They propose that the Svep1 protein regulates, in part, FGF9 signalling. Overall, the paper demonstrates that the ECM is important for lung development and tries to implicate the ECM in the regulation of epithelial-mesenchymal interactions during lung development.
Strengths:
The strengths of this paper are the careful spatiotemporal characterization of 1) lung growth 2) branching morphogenesis 3) epithelial marker expression. The differential perturbation of growth and branching morphogenesis along the D-V axis and the progressive perturbation of branching morphogenesis are both very interesting and noteworthy phenotypes.
Weaknesses:
The weakness of this paper is that it does not present a convincing explanation for how Svep1 regulates any of the phenotypes described. In this regard, a demonstration of a genetic interaction between Svep1 and FGF9 mutants or a careful characterization of a tissue-specific knockdown of Svep1, could be insightful. In addition, a comparison of the phenotype of Svep1 mutants and the phenotypes of other mutants affecting ECM components would be worthwhile.
A minor weakness is that the title of the paper is not fully supported by the data presented. While the defects in the morphogenesis of the distal lung in Svep1 mutants presage a defect in alveolar differentiation, this cannot be formally demonstrated since the animals die soon after birth.