Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia
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 conseque...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/77522 |
| _version_ | 1811238191237169152 |
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| author | Feng Gao Changgong Li Susan M Smith Neil Peinado Golenaz Kohbodi Evelyn Tran Yong-Hwee Eddie Loh Wei Li Zea Borok Parviz Minoo |
| author_facet | Feng Gao Changgong Li Susan M Smith Neil Peinado Golenaz Kohbodi Evelyn Tran Yong-Hwee Eddie Loh Wei Li Zea Borok Parviz Minoo |
| author_sort | Feng Gao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:37:35Z |
| format | Article |
| id | doaj.art-a0892f126aa541e9893871d7c3283441 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:37:35Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a0892f126aa541e9893871d7c32834412022-12-22T03:32:52ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.77522Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasiaFeng Gao0https://orcid.org/0000-0001-8764-1107Changgong Li1Susan M Smith2Neil Peinado3Golenaz Kohbodi4Evelyn Tran5Yong-Hwee Eddie Loh6Wei Li7Zea Borok8https://orcid.org/0000-0001-8673-8177Parviz Minoo9Division of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, United StatesDivision of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, United StatesDivision of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, United StatesDivision of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, United StatesDivision of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, United StatesNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, United States; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United StatesNorris Medical Library, University of Southern California, Los Angeles, United StatesDepartment of Nephrology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, ChinaDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, San Diego, United StatesDivision of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, United States; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, United StatesLung 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.https://elifesciences.org/articles/77522developmental GRNalveologenesisIGF1 signalingbronchopulmonary dysplasia |
| spellingShingle | Feng Gao Changgong Li Susan M Smith Neil Peinado Golenaz Kohbodi Evelyn Tran Yong-Hwee Eddie Loh Wei Li Zea Borok Parviz Minoo Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia eLife developmental GRN alveologenesis IGF1 signaling bronchopulmonary dysplasia |
| title | Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia |
| title_full | Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia |
| title_fullStr | Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia |
| title_full_unstemmed | Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia |
| title_short | Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia |
| title_sort | decoding the igf1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia |
| topic | developmental GRN alveologenesis IGF1 signaling bronchopulmonary dysplasia |
| url | https://elifesciences.org/articles/77522 |
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