TY - JOUR
T1 - Aerocyte specification and lung adaptation to breathing is dependent on alternative splicing changes
AU - Fidalgo, Marta F.
AU - Fonseca, Catarina G.
AU - Caldas, Paulo
AU - Raposo, Alexandre A. S. F.
AU - Balboni, Tania
AU - Henao-Mišíková, Lenka
AU - Grosso, Ana R.
AU - Vasconcelos, Francisca F.
AU - Franco, Cláudio A.
N1 - Publisher Copyright:
© 2022 Fidalgo et al.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Adaptation to breathing is a critical step in lung function and it is crucial for organismal survival. Alveoli are the lung gas exchange units and their development, from late embryonic to early postnatal stages, requires feedbacks between multiple cell types. However, how the crosstalk between the alveolar cell types is modulated to anticipate lung adaptation to breathing is still unclear. Here, we uncovered a synchronous alternative splicing switch in multiple genes in the developing mouse lungs at the transition to birth, and we identified hnRNP A1, Cpeb4, and Elavl2/HuB as putative splicing regulators of this transition. Notably, we found that Vegfa switches from the Vegfa 164 isoform to the longer Vegfa 188 isoform exclusively in lung alveolar epithelial AT1 cells. Functional analysis revealed that VEGFA 188 (and not VEGFA 164) drives the specification of Car4-positive aerocytes, a subtype of alveolar endothelial cells specialized in gas exchanges. Our results reveal that the cell type-specific regulation of Vegfa alternative splicing just before birth modulates the epithelial-endothelial crosstalk in the developing alveoli to promote lung adaptation to breathing.
AB - Adaptation to breathing is a critical step in lung function and it is crucial for organismal survival. Alveoli are the lung gas exchange units and their development, from late embryonic to early postnatal stages, requires feedbacks between multiple cell types. However, how the crosstalk between the alveolar cell types is modulated to anticipate lung adaptation to breathing is still unclear. Here, we uncovered a synchronous alternative splicing switch in multiple genes in the developing mouse lungs at the transition to birth, and we identified hnRNP A1, Cpeb4, and Elavl2/HuB as putative splicing regulators of this transition. Notably, we found that Vegfa switches from the Vegfa 164 isoform to the longer Vegfa 188 isoform exclusively in lung alveolar epithelial AT1 cells. Functional analysis revealed that VEGFA 188 (and not VEGFA 164) drives the specification of Car4-positive aerocytes, a subtype of alveolar endothelial cells specialized in gas exchanges. Our results reveal that the cell type-specific regulation of Vegfa alternative splicing just before birth modulates the epithelial-endothelial crosstalk in the developing alveoli to promote lung adaptation to breathing.
UR - http://www.scopus.com/inward/record.url?scp=85139692081&partnerID=8YFLogxK
U2 - 10.26508/lsa.202201554
DO - 10.26508/lsa.202201554
M3 - Article
C2 - 36220570
AN - SCOPUS:85139692081
SN - 2575-1077
VL - 5
JO - Life Science Alliance
JF - Life Science Alliance
IS - 12
M1 - e202201554
ER -