Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia

Author:

Gao Feng1ORCID,Li Changgong1,Smith Susan M1,Peinado Neil1,Kohbodi Golenaz1,Tran Evelyn23,Loh Yong-Hwee Eddie4,Li Wei5,Borok Zea6ORCID,Minoo Parviz17

Affiliation:

1. Division of Neonatology, Department of Pediatrics, University of Southern California

2. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California

3. Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California

4. Norris Medical Library, University of Southern California

5. Department of Nephrology, Jiangsu Provincial Hospital of Traditional Chinese Medicine

6. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego

7. Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California

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.

Funder

National Heart, Lung, and Blood Institute

Hastings Foundation

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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