Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia
- University of Southern California, United States
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, China
- University of California, San Diego, United States
Abstract
Lung development is precisely controlled by underlying Gene Regulatory Networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD)–a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin’s development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird’s-eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.
Data availability
Sequencing data generated for this study have been deposited in GEO under the accession code GSE182886.All other data generated or analyzed during this study are included in the manuscript and supporting files.Source Data files have been provided in Figure 3-Source Data 1&2, Figure 4-Source Data 1&2, and Figure 6-Source Data 1.An online repository of the network and the data presented in this paper has been made available to the public at https://sites.google.com/view/the-alveologenesis-grn/home.
-
Decoding A Gene Regulatory Network Behind Bronchopulmonary DysplasiaNCBI Gene Expression Omnibus, GSE182886.
-
The single cell RNA seq of pulmonary alveolar epithelial cellsNCBI Gene Expression Omnibus, GSE106960.
-
A Single Cell Atlas of Alveolar DevelopmentNCBI Gene Expression Omnibus, GSEGSE165063.
-
Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epitheliumNCBI Gene Expression Omnibus, GSEGSE160876.
-
The genomic, epigenomic and biophysical cues controlling the emergence of the gas exchange niche in the lungNCBI Gene Expression Omnibus, GSE149563.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (5R01HL144932-04)
- Changgong Li
National Heart, Lung, and Blood Institute (5R01HL143059-04)
- Parviz Minoo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: BPD and non-BPD postnatal human lung tissues were provided by the International Institute for the Advancement of Medicine and the National Disease Research Interchange, and were classified exempt from human subject regulations per the University of Rochester Research Subjects Review Board protocol (RSRB00056775).
Copyright
© 2022, Gao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 896
- views
-
- 172
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia
eLife 11:e77522.
https://doi.org/10.7554/eLife.77522
Further reading
-
- Cell Biology
G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
