β-Catenin maintains lung epithelial progenitors after lung specification

Ostrin, Edwin J.; Little, Danielle R.; Gerner-Mauro, Kamryn N.; Sumner, Elizabeth; Ríos-Corzo, Ricardo; Ambrosio, Elizabeth Mayela; Holt, Samantha E.; Forcioli-Conti, Nicolas R.; Akiyama, Haruhiko; Hanash, Sam; Kimura, Shioko; Huang, Sarah X.L.; Chen, Jichao

doi:10.1242/dev.160788

Cited by 47 publications

(74 citation statements)

References 53 publications

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“…These morphological and molecular changes largely phenocopied the post-lungspecification Ctnnb1 mutant (11). Such similarity was reinforced by the same downregulation of additional, but not all, progenitor genes (as exemplified by Etv5 and Bmp4, respectively), premature expression of an alveolar differentiation gene Sftpb, and ectopic expression of a gastrointestinal gene Alb (Fig.…”

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 77%

“…Such similarity was reinforced by the same downregulation of additional, but not all, progenitor genes (as exemplified by Etv5 and Bmp4, respectively), premature expression of an alveolar differentiation gene Sftpb, and ectopic expression of a gastrointestinal gene Alb (Fig. 3C) (11). However, unlike the Ctnnb1 mutant, NKX2-1 expression was unaffected even when Lef/Tcf recombination was induced early at E11 (Fig.…”

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 83%

“…The lung epithelial primordium originates from the anterior foregut as a group of NKX2-1/SOX9 double positive progenitors, which remain distally during subsequent branching morphogenesis, leaving behind SOX2-expressing progeny for the airways early in development and alveolar cells late in development (12). The established role of canonical Wnt signaling components, CTNNB1 and WNT2/2B, in specifying and maintaining these lung progenitors (9)(10)(11) provides an in vivo system to investigate the 4 corresponding transcription factor paralogs: LEF1, TCF7, TCF7L1, and TCF7L2 (6). We set out to identify which LEF/TCF was present in the epithelium using immunostaining, and found that while all 4 factors were expressed in the surrounding mesenchyme, only TCF7L1 and TCF7L2 were readily detectible in the epithelium (Fig.…”

Section: Tcf7l1 and Tcf7l2 The Main Lef/tcf Factors In The Lung Epitmentioning

confidence: 99%

“…Since the Shh Cre quadruple mutant barely formed a lung, we sought to characterize the function of Lef/Tcf in the progenitors by deleting all 4 paralogs with Sox9 CreER after lung specification, as we have done to study CTNNB1 (11). When recombination was induced at E11, progenitor branching was compromised, as reflected in the characteristic dilation of branch tips, in association with downregulation of SOX9 ( Fig.…”

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 99%

“…3C). This might be because it took longer to recombine all 8 alleles when NKX2-1 expression no longer depended on Wnt signaling, as supported by its normal expression when Ctnnb1 was deleted at E13 (11). Taken together, Lef/Tcf paralogs, similar to CTNNB1, maintain lung epithelial progenitors by promoting a subset of progenitor genes and repressing genes associated with alveolar and gastrointestinal differentiation.…”

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 99%

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Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors

Gerner-Mauro

Akiyama

Chen

2020

Preprint

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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 multi-member paralogs, as exemplified by the 4 obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the dauntingly complex genetics involved. Using the developing mouse lung as a model system, we generate 2 quadruple conditional knockouts and myriad triple and double combinations, and show that the 4 Lef/Tcf genes function redundantly in the presence of at least 2 Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Pre-lung-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 4 Lef/Tcf genes leads to branching defects, downregulation 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 and represents, to our knowledge, the first in vivo analysis of cell-type-specific genetic redundancy among the 4 Lef/Tcf paralogs. SIGNIFICANCE STATEMENTParalogs represent genetic redundancy and survive purifying selection by evolving overlapping and distinct functions. In multicellular organisms, such functional diversification can manifest as tissue and cell type specific expression, which masks possible selective pressure for genetic redundancy within a single cell type. Using in vivo genetic and genomic analyses, we show that although the 4 mammalian Lef/Tcf transcription factors have evolved organ-specific functions, they function additively and redundantly, depending on gene dosage, to promote lung epithelial progenitors and do so in a monotonic, positive manner with beta-Catenin in the canonical Wnt signaling pathway.

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Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 77%

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 83%

Section: Tcf7l1 and Tcf7l2 The Main Lef/tcf Factors In The Lung Epitmentioning

confidence: 99%

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 99%

Section: Lef1/tcf7/tcf7l1/tcf7l2 Maintain Epithelial Progenitorsmentioning

confidence: 99%

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Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors

Gerner-Mauro

Akiyama

Chen

2020

Preprint

Self Cite

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Lung patterning: Is a distal‐to‐proximal gradient of cell allocation and fate decision a general paradigm?

Zhang,

Aung,

Yao

et al. 2023

BioEssays

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Recent studies support a model in which the progeny of SOX9+ epithelial progenitors at the distal tip of lung branches undergo cell allocation and differentiation sequentially along the distal‐to‐proximal axis. Concomitant with the elongation and ramification of lung branches, the descendants of the distal SOX9+ progenitors are distributed proximally, express SOX2, and differentiate into cell types in the conducting airways. Amid subsequent sacculation, the distal SOX9+ progenitors generate alveolar epithelial cells to form alveoli. Sequential cell allocation and differentiation are integrated with the branching process to generate a functional branching organ. This review focuses on the roles of SOX9+ cells as precursors for new branches, as the source of various cell types in the conducting airways, and as progenitors of the alveolar epithelium. All of these processes are controlled by multiple signaling pathways. Many mouse mutants with defective lung branching contain underlying defects in one or more steps of cell allocation and differentiation of SOX9+ progenitors. This model provides a framework to understand the molecular basis of lung phenotypes and to elucidate the molecular mechanisms of lung patterning. It builds a foundation on which comparing and contrasting the mechanisms employed by different branching organs in diverse species can be made.

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Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis

Ikonomou

Yampolskaya

Mehta

2023

Advances in Experimental Medicine and Biology

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Transient, tissue-specific, embryonic progenitors are important cell populations in vertebrate development. In the course of respiratory system development, multipotent mesenchymal and epithelial progenitors drive the diversification of fates that results to the plethora of cell types that compose the airways and alveolar space of the adult lungs. Use of mouse genetic models, including lineage tracing and loss-of-function studies, has elucidated signaling pathways that guide proliferation and differentiation of embryonic lung progenitors as well as transcription factors that underlie lung progenitor identity. Furthermore, pluripotent stem cell-derived and ex vivo expanded respiratory progenitors offer novel, tractable, high-fidelity systems that allow for mechanistic studies of cell fate decisions and developmental processes. As our understanding of embryonic progenitor biology deepens, we move closer to the goal of in vitro lung organogenesis and resulting applications in developmental biology and medicine.

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β-Catenin maintains lung epithelial progenitors after lung specification

Cited by 47 publications

References 53 publications

Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors

Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors

Lung patterning: Is a distal‐to‐proximal gradient of cell allocation and fate decision a general paradigm?

Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis

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