Proper lung function relies on the precise balance of specialized epithelial cell types that coordinate to maintain homeostasis. The Hippo pathway has emerged as a critical regulator of cell fate both developmentally and in a regenerative setting. The work presented in this dissertation describes essential roles for the transcriptional effectors of Hippo pathway signaling, Yap and Taz, in maintaining lung epithelial homeostasis. The data presented here demonstrate that conditional deletion of 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 disorganization, a development of mucin hypersecretion throughout the airways, and ciliary disorganization. Through in vivo lineage tracing, analysis of mouse and human tissues, along with in vitro molecular experiments, these studies show that nuclear YAP/TAZ exert transcriptional control over club cell fate, while in multiciliated cells, they function within the cytoplasm to maintain ciliary structures. Within club cells, reduced YAP/TAZ activity promotes intrinsic goblet transdifferentiation of secretory airway epithelial cells. Global gene expression and ChIP-Seq analyses reveal that YAP/TAZ act through the TEAD family of transcription factors to suppress a goblet cell differentiation program in airway epithelial cells, including direct repression of the SPDEF gene, which encodes a transcription factor required for goblet cell identity. Further in vitro studies identify cooperation between YAP/TAZ-TEAD and the NuRD chromatin remodeling complex to inhibit SPDEF expression and that Hippo-regulated YAP/TAZ impinge on cytokine-induced goblet cell differentiation. Within multiciliated cells, we observe that phosphorylated Yap localizes in a planar polarized manner at the base of cilia and controls ciliary and basal body density. Lineage specific Yap/Taz deletion leads to reduced ciliary density and height due to a loss of apically basal bodies. Collectively, this work identifies YAP/TAZ as critical factors in lung epithelial homeostasis and offers new molecular insight into the mechanisms regulating the secretory and multiciliated cell lineages, which are frequently impaired in a broad range of lung diseases. / 2024-02-02T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/43766 |
| Date | 02 February 2022 |
| Creators | Hicks-Berthet, Julia Bellows |
| Contributors | Varelas, Xaralabos |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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