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

  1. Feng Gao  Is a corresponding author
  2. Changgong Li
  3. Susan M Smith
  4. Neil Peinado
  5. Golenaz Kohbodi
  6. Evelyn Tran
  7. Yong-Hwee Eddie Loh
  8. Wei Li
  9. Zea Borok
  10. Parviz Minoo  Is a corresponding author
  1. University of Southern California, United States
  2. Jiangsu Provincial Hospital of Traditional Chinese Medicine, China
  3. 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.

The following data sets were generated
The following previously published data sets were used
    1. The LungMAP Consortium
    (2019) LungMAP Consortium Data
    NCBI Gene Expression Omnibus, GSE128810.

Article and author information

Author details

  1. Feng Gao

    Department of Pediatrics, University of Southern California, Los Angeles, United States
    For correspondence
    fremontgao@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8764-1107
  2. Changgong Li

    Department of Pediatrics, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Susan M Smith

    Department of Pediatrics, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Neil Peinado

    Department of Pediatrics, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Golenaz Kohbodi

    Department of Pediatrics, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Evelyn Tran

    Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yong-Hwee Eddie Loh

    USC Libraries Bioinformatics Services, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Wei Li

    Department of Nephrology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Zea Borok

    Department of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8673-8177
  10. Parviz Minoo

    Department of Pediatrics, University of Southern California, Los Angeles, United States
    For correspondence
    minoo@usc.edu
    Competing interests
    The authors declare that no competing interests exist.

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).

Reviewing Editor

  1. Nicholas E Banovich, Translational Genomics Research Institute, United States

Version history

  1. Preprint posted: January 25, 2022 (view preprint)
  2. Received: February 2, 2022
  3. Accepted: October 7, 2022
  4. Accepted Manuscript published: October 10, 2022 (version 1)
  5. Accepted Manuscript updated: October 11, 2022 (version 2)
  6. Version of Record published: October 19, 2022 (version 3)

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.

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  1. Feng Gao
  2. Changgong Li
  3. Susan M Smith
  4. Neil Peinado
  5. Golenaz Kohbodi
  6. Evelyn Tran
  7. Yong-Hwee Eddie Loh
  8. Wei Li
  9. Zea Borok
  10. Parviz Minoo
(2022)
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

Share this article

https://doi.org/10.7554/eLife.77522

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