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Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia

Gao, F. and Li, C. and Smith, S. M. and Peinado, N. and Kohbodi, G. and Tran, E. and Loh, E. and Li, W. and Peter, I. and Borok, Z. and Minoo, P. (2022) Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia. Cold Spring Harbor Laboratory . (Unpublished)

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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 that is 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 of 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. The 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.

Item Type:Report or Paper (Discussion Paper)
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Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Version 1 - January 25, 2022; Version 2 - February 2, 2022. We thank Dr. Andrew P. McMahon (Keck School of Medicine of USC) for providing the Foxd1GCE;CAG^(tdTomato) mice. We thank Arnold Sipos (Keck School of Medicine of USC) for help with imaging and Sean Gao (Arcadia High School) for data analysis and the construction of alveologenesis GRN website. Fundings: This work was supported by the National Institutes of Health [HL144932, HL122764 (C.L. & P.M.), HL143059 (P.M.), R35 HL135747 (Z.B. & P.M.)], the Hastings Foundation (P.M., Z.B.). Author Contributions: Conceptualization: F.G., C.L., P.M.; Data curation: F.G., C.L., P.M.; Investigation: F.G., C.L., S.M.S., N.P., G.K., E.T., E.L., W.L.; Methodology: F.G., C.L., P.M.; Validation: F.G., C.L., P.M.; Project administration: C.L., P.M.; Funding acquisition: C.L., P.M.; Writing – original draft: F.G., P.M.; Writing – review & editing: F.G., P.M., C.L., E.T., I.P., B.Z. The authors have declared no competing interest. Data Availability Statement: Additional data that support the findings of this study are available on request from the corresponding author.
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NIHR35 HL135747
Hastings FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20220204-651687100
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Official Citation:Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia. F Gao, C Li, SM Smith, N Peinado, G Kohbodi, E Tran, E Loh, W Li, I Peter, Z Borok, P Minoo. bioRxiv 2022.01.24.477613; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113273
Deposited By: Tony Diaz
Deposited On:04 Feb 2022 16:52
Last Modified:04 Feb 2022 16:52

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