TY - JOUR
T1 - Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors
AU - Gerner-Mauro, Kamryn N.
AU - Akiyama, Haruhiko
AU - Chen, Jichao
N1 - Funding Information:
We thank Dr. Hai-Hui Xue (University of Iowa) for sharing the Lef1LoxP and Tcf7LoxP mice, Dr. Elaine Fuchs (Rockefeller University) and Dr. Hoang Nguyen (Baylor College of Medicine) for sharing the Tcf7l1LoxP mice, and Drs. Mario Capecchi and Melinda Angus-Hill (University of Utah) for sharing the Tcf7l2LoxP mice. We thank Dr. Hoang Nguyen (Baylor College of Medicine) for sharing the TCF7L1 antibody. The University of Texas MD Anderson Cancer Center DNA Analysis Facility and Flow Cytometry and Cellular Imaging Core Facility are supported by the Cancer Center Support Grant (CA No. 16672). This work was supported by the University of Texas MD Anderson Cancer Center Start-up and Retention Fund, an Institutional Research Grant, and National Institutes of Health R01HL130129 (J.C.).
Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Hai-Hui Xue (University of Iowa) for sharing the Lef1LoxP and Tcf7LoxP mice, Dr. Elaine Fuchs (Rockefeller University) and Dr. Hoang Nguyen (Baylor College of Medicine) for sharing the Tcf7l1LoxP mice, and Drs. Mario Capecchi and Melinda Angus-Hill (University of Utah) for sharing the Tcf7l2LoxP mice. We thank Dr. Hoang Nguyen (Baylor College of Medicine) for sharing the TCF7L1 antibody. The University of Texas MD Anderson Cancer Center DNA Analysis Facility and Flow Cytometry and Cellular Imaging Core Facility are supported by the Cancer Center Support Grant (CA No. 16672). This work was supported by the University of Texas MD Anderson Cancer Center Start-up and Retention Fund, an Institutional Research Grant, and National Institutes of Health R01HL130129 (J.C.).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/2
Y1 - 2020/6/2
N2 - In multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multimember paralogs, as exemplified by the four obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the complex genetics involved. Using the developing mouse lung as a model system, we generate two quadruple conditional knockouts, four triple mutants, and various combinations of double mutants, showing that the four Lef/Tcf genes function redundantly in the presence of at least two Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Prelung-specification, pan-epithelial double knockouts have no lung phenotype; triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas; and the quadruple knockout barely forms a lung, resembling the Ctnnb1 mutant. Postlung-specification deletion of all four Lef/Tcf genes leads to branching defects, down-regulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the corresponding Ctnnb1 mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors as opposed to reported repressor functions of Lef/Tcf, and represents a thorough in vivo analysis of cell-type-specific genetic redundancy among the four Lef/Tcf paralogs.
AB - In multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multimember paralogs, as exemplified by the four obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the complex genetics involved. Using the developing mouse lung as a model system, we generate two quadruple conditional knockouts, four triple mutants, and various combinations of double mutants, showing that the four Lef/Tcf genes function redundantly in the presence of at least two Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Prelung-specification, pan-epithelial double knockouts have no lung phenotype; triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas; and the quadruple knockout barely forms a lung, resembling the Ctnnb1 mutant. Postlung-specification deletion of all four Lef/Tcf genes leads to branching defects, down-regulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the corresponding Ctnnb1 mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors as opposed to reported repressor functions of Lef/Tcf, and represents a thorough in vivo analysis of cell-type-specific genetic redundancy among the four Lef/Tcf paralogs.
KW - Epithelial progenitors
KW - Gene duplication
KW - Lef/Tcf transcription factors
KW - Lung development
KW - Wnt signaling
UR - https://www.scopus.com/pages/publications/85085909604
UR - https://www.scopus.com/pages/publications/85085909604#tab=citedBy
U2 - 10.1073/pnas.2002082117
DO - 10.1073/pnas.2002082117
M3 - Article
C2 - 32414917
AN - SCOPUS:85085909604
SN - 0027-8424
VL - 117
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
ER -