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Dynamic Hippo pathway activity underlies mesenchymal differentiation during lung alveolar morphogenesis [bulk RNA-seq]

ABSTRACT: Alveologenesis, the final stage in lung development, substantially remodels the distal lung, expanding the alveolar surface area for efficient gas exchange. Secondary crest myofibroblasts (SCMF) exist transiently in the neonatal distal lung and are critical for alveologenesis. However, the pathways that regulate SCMF function, proliferation, and temporal identity remain poorly understood. To address this, we purified SCMFs from reporter mice, performed bulk RNA-sequencing, and found dynamic changes in Hippo-signaling components during alveologenesis. We deleted Hippo effectors, Yap/Taz, from Acta2-expressing SCMFs at the onset of alveologenesis, causing a significant arrest in alveolar development. Using scRNA-seq, we identified a distinct cluster of cells in mutant lungs with altered expression of marker genes associated with proximal mesenchymal cell types, airway smooth muscle (ASM), and alveolar duct myofibroblasts (DMF). Using lineage tracing, we show that neonatal Acta2-expressing SCMFs give rise to adult DMFs and that Yap/Taz mutants have an increase of persisting DMF-like cells in the alveolar ducts. Our findings identify aberrant differentiation of neonatal lung myofibroblasts and demonstrate that Yap/Taz are critical for maintaining lineage commitment.

ORGANISM(S): Mus musculus

PROVIDER: GSE255059 | GEO | 2024/02/10

REPOSITORIES: GEO

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Dynamic Hippo pathway activity underlies mesenchymal differentiation during lung alveolar morphogenesis

Project description:Alveologenesis, the final stage in lung development, substantially remodels the distal lung, expanding the alveolar surface area for efficient gas exchange. Secondary crest myofibroblasts (SCMF) exist transiently in the neonatal distal lung and are critical for alveologenesis. However, the pathways that regulate SCMF function, proliferation, and temporal identity remain poorly understood. To address this, we purified SCMFs from reporter mice, performed bulk RNA-sequencing, and found dynamic changes in Hippo-signaling components during alveologenesis. We deleted Hippo effectors, Yap/Taz, from Acta2-expressing SCMFs at the onset of alveologenesis, causing a significant arrest in alveolar development. Using scRNA-seq, we identified a distinct cluster of cells in mutant lungs with altered expression of marker genes associated with proximal mesenchymal cell types, airway smooth muscle (ASM), and alveolar duct myofibroblasts (DMF). Using lineage tracing, we show that neonatal Acta2-expressing SCMFs give rise to adult DMFs and that Yap/Taz mutants have an increase of persisting DMF-like cells in the alveolar ducts. Our findings identify aberrant differentiation of neonatal lung myofibroblasts and demonstrate that Yap/Taz are critical for maintaining lineage commitment.

2024-02-10 | GSE255060 | GEO

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Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. We describe essential roles for the transcriptional regulators Yap and Taz, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. We report that conditional deletion of Yap1/Yap and Wwtr1/Taz in the lung epithelium of adult mice results in severe defects with consequent animal lethality. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. We performed gene expression analysis of wild type and Yap/Taz null primary mouse airway epithelial cells in order to define Yap/Taz controlled gene expression.

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2021-08-19 | GSE158306 | GEO

Yap/Taz inhibit goblet cell fate to maintain lung epithelial homeostasis (RNA-seq)

Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. In this study we have described essential roles for the transcriptional regulators YAP and TAZ, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. Knockdown of YAP and TAZ in HBECs similarly drives mucin expression. The TEAD family of transcription factors are well characterized partners of the YAP/TAZ transcriptional effectors, and we have found that knockdown of TEAD1-4 similarly drives elevated mucin expression. In order to further understand the role of the TEAD transcription factors in human lung epithelial cell fate, we conducted TEAD Chromatin Immunopreciptitation (ChIP)-Sequencing.

2021-08-19 | GSE158305 | GEO

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2024-04-17 | GSE261508 | GEO

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Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.

2017-06-20 | E-MTAB-5395 | biostudies-arrayexpress

The effect of YAP/TAZ knockdown on the intestinal epithelium

Project description:The Hippo pathway plays a crucial in organ size control during development and tissue homeostasis in adult life. To examine a role for Hippo signaling in the intestinal epithelium, we analyzed gene expression patterns in the mouse intestinal epithelilum transfected with siRNAs or expression plasmids for shRNAs targeting the Hippo pathway effectors, YAP and TAZ. We performed two independent series of experiments (siGFP (n=3) vs siYAP/siTAZ (n=3), and shLacZ (n=1) vs shYAP/shTAZ (n=1)). Control siRNA (siGFP), YAP/TAZ siRNAs, or expression plasmids for control shRNA (shLacZ) or YAP/TAZ shRNAs were introduced into the mouse intestinal epithelium by the newly-developed in vivo transfection method. Four days after transfection, intestinal epithelial cells were isolated from the tissues and total RNA was extracted.

2014-07-18 | E-GEOD-45155 | biostudies-arrayexpress

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