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Alternative splicing changes are associated with pre-birth adaptation during lung development

View ORCID ProfileMarta F. Fidalgo, View ORCID ProfileCatarina G. Fonseca, View ORCID ProfilePaulo Caldas, View ORCID ProfileAlexandre A. S. F. Raposo, View ORCID ProfileTania Balboni, View ORCID ProfileAna R. Grosso, View ORCID ProfileFrancisca F. Vasconcelos, View ORCID ProfileCláudio A. Franco
doi: https://doi.org/10.1101/2022.01.19.476886
Marta F. Fidalgo
1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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Catarina G. Fonseca
1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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Paulo Caldas
2UCIBIO – Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
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Alexandre A. S. F. Raposo
1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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Tania Balboni
3Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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Ana R. Grosso
2UCIBIO – Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal
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Francisca F. Vasconcelos
1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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  • For correspondence: fvasconcelos@medicina.ulisboa.pt cfranco@medicina.ulisboa.pt
Cláudio A. Franco
1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
4Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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  • For correspondence: fvasconcelos@medicina.ulisboa.pt cfranco@medicina.ulisboa.pt
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Abstract

Gas exchanges are ensured by lung alveoli, which are mainly composed by epithelial alveolar type 1 (AT1), alveolar type 2 (AT2) and capillary endothelial cells (ECs). Alveologenesis starts during late embryonic development and continues after birth and relies on extensive biochemical crosstalk between these cell types. How this crosstalk is modulated to anticipate and accommodate the radical changes occurring at birth is still unclear.

We investigated the alternative splicing (AS) changes occurring during lung development at the embryonic to postnatal transition by performing RNAseq of mouse lungs at distinct developmental stages. We found that most of the AS changes occur at the embryonic to postnatal transition. In addition, we identified hnRNP A1, Cpeb4 and Elavl2/HuB as putative splicing regulators of this transition. We show that the AS of a major pro- angiogenic chemokine, vascular endothelial growth factor A (VEGFA), is differentially regulated at this transition. Remarkably, we found that there is a switch from the predominance of Vegfa 164 to Vegfa 188 just before birth specifically in AT1 cells, whilst in other cell populations Vegfa does not undergo AS changes. Moreover, we identified a novel Vegfa isoform generated by the retention of intron 5, Vegfa i5.

Our results reveal a cell type-specific regulation of Vegfa AS that may constitute a pre- birth adaptation mechanism of the epithelial-endothelial crosstalk, which may be fundamental for the adaptation to breathing and may have implications for pathological conditions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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 4.0 International license.
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Posted January 21, 2022.
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Alternative splicing changes are associated with pre-birth adaptation during lung development
Marta F. Fidalgo, Catarina G. Fonseca, Paulo Caldas, Alexandre A. S. F. Raposo, Tania Balboni, Ana R. Grosso, Francisca F. Vasconcelos, Cláudio A. Franco
bioRxiv 2022.01.19.476886; doi: https://doi.org/10.1101/2022.01.19.476886
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Alternative splicing changes are associated with pre-birth adaptation during lung development
Marta F. Fidalgo, Catarina G. Fonseca, Paulo Caldas, Alexandre A. S. F. Raposo, Tania Balboni, Ana R. Grosso, Francisca F. Vasconcelos, Cláudio A. Franco
bioRxiv 2022.01.19.476886; doi: https://doi.org/10.1101/2022.01.19.476886

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