The Hippo pathway in organ development, homeostasis, and regeneration

Fu, Vivian; Plouffe, Steven W.; Guan, Kun‐Liang

doi:10.1016/j.ceb.2017.12.012

Cited by 197 publications

(156 citation statements)

References 63 publications

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“…Transcription of the Nlrc4 gene is controlled by the p73-YAP heterodimer. Yes-associated protein (YAP) is a pro-apoptotic transcriptional coactivator that acts within the Hippo pathway and regulates cell proliferation, cell differentiation, spatial organ patterning and tissue regeneration [26]. Furthermore, YAP potentiates p73 function as a transcription factor [27–29].…”

Section: Introductionmentioning

confidence: 99%

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

et al. 2018

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B cells are a target of Salmonella infection, allowing bacteria survival without inducing pyroptosis. This event is due to downregulation of Nlrc4 expression and lack of inflammasome complex activation, which impairs the secretion of IL-1β. YAP phosphorylation is required for downregulation of Nlrc4 in B cells during Salmonella infection; however, the microorganism’s mechanisms underlying the inhibition of the NLRC4 inflammasome in B cells are not fully understood. Our findings demonstrate that the Salmonella effector SopB triggers a signaling cascade involving PI3K, PDK1 and mTORC2 that activates Akt with consequent phosphorylation of YAP. When we deleted sopB in Salmonella, infected B cells that lack Rictor, or inhibited the signaling cascade using a pharmacological approach, we were able to restore the function of the NLRC4 inflammasome in B cells and the ability to control the infection. Furthermore, B cells from infected mice exhibited activation of Akt and YAP phosphorylation, suggesting that Salmonella also triggers this pathway in vivo. In summary, our data demonstrate that the Salmonella effector inositide phosphate phosphatase SopB triggers the PI3K-Akt-YAP pathway to inhibit the NLRC4 inflammasome in B cells. This study provides further evidence that Salmonella triggers cellular mechanisms in B lymphocytes to manipulate the host environment by turning it into a survival niche to establish a successful infection.

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Section: Introductionmentioning

confidence: 99%

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

et al. 2018

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“…Both are transcriptional coactivators of TEAD family transcription factors. Originally identified in Drosophila as a regulator of organ growth, the Hippo pathway progressively emerged as a key signaling in a wide range of biological processes 9 , including stem cell biology 10,11 . Of note, it proved to be dispensable under physiological conditions in some adult stem cells, such as mammary gland, pancreatic, intestinal and, importantly, neural stem cells [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Linking YAP to Müller glia quiescence exit in the degenerative retina

Hamon

Ail

García-García

et al. 2018

Preprint

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Contrasting with fish or amphibian, retinal regeneration from Müller glial cells is largely limited in mammals. In our quest towards the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP, which we previously found to be upregulated in Müller cells following retinal injury. We report that conditional Yap deletion in Müller cells prevents the upregulation of cell cycle genes that normally accompanies reactive gliosis upon photoreceptor cell death. This occurs as a consequence of defective EGFR signaling. Consistent with a function of YAP in triggering Müller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injurydependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Müller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Müller cell response to injury and highlight a novel YAP-EGFR axis by which Müller cells exit their quiescence state, a critical step towards regeneration. Key words: Müller cells, reactive gliosis, retinal regeneration, Hippo/YAP pathway, EGFRpathway Neurodegenerative retinal diseases, such as retinitis pigmentosa or age-related macular degeneration, ultimately lead to vision loss, as a consequence of photoreceptor cell death. Driving retinal self-repair from endogenous neural stem cells in patients represents an attractive therapeutic strategy. Among cellular sources of interest are Müller cells, the major glial cell type in the retina. These cells are essential for maintaining retinal homeostasis 1 but also proved their potential for endogenous regeneration. In certain species, such as zebrafish or Xenopus, they behave as genuine stem cells, endowed with the ability to reprogram into a progenitor-like state upon retinal damage, proliferate and regenerate lost photoreceptors 2-4 . In mammals, however, their proliferative response to injury is extremely limited. Following acute retinal damage, mouse Müller glial cells rapidly re-enter G1-phase of the cell cycle, as inferred by increased cyclin gene expression, but they rarely divide 5 . Suggesting that they nonetheless retain remnants of repair capacities, their proliferation and neurogenic potential can be stimulated, for instance by supplying exogenous growth factors such as Heparin-binding EGF-like growth factor (HB-EGF), or by overexpressing the proneural gene Ascl1a 3,6-8 . Our understanding of the genetic/signaling network sustaining Müller cell stemness potential is however far from being complete. Identifying novel molecular cues is thus of utmost importance to foresee putative candidates that could be targeted for regenerative medicine. We here investigated whether the Hippo pathway effector YAP might influence Müller cell reactivation and how it would intersect with other critical signaling pathways. The Hippo pathway is a kina...

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“…Inactivation of Tead4 leads to all cells adopting the inner cell mass fate (19). Hippo subsequently acts in different progenitor cell types to direct fate specification in a variety of embryonic and adult tissues (20). For instance, in the liver, the differentiation of hepatoblasts and progenitor cells into either hepatocytes or cholangiocytes is determined by YAP and TAZ expression and activity (21,22).…”

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confidence: 99%

Lats1andLats2are required for ovarian granulosa cell fate maintenance

et al. 2019

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Recent reports suggest that the Hippo signaling pathway influences ovarian follicle development; however, its exact roles remain unknown. Here, we examined the ovarian functions of the Hippo kinases large tumor suppressors (LATS)1 and 2, which serve to inactivate the transcriptional coactivators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ). Inactivation of Lats1/2 in murine granulosa cells either in vitro or in vivo resulted in a loss of granulosa cell morphology, function, and gene expression. Mutant cells further underwent changes in structure and gene expression suggestive of epithelial‐to‐mesenchymal transition and transdifferentiation into multiple lineages. In vivo, granulosa cell‐specific loss of Lats1/2 caused the ovarian parenchyma to be mostly replaced by bone tissue and seminiferous tubule‐like structures. Transdifferentiation into Sertoli‐like cells and osteoblasts was attributed in part to the increased recruitment of YAP and TAZ to the promoters of sex‐determining region Y box 9 and bone γ‐carboxyglutamate protein, key mediators of male sex determination and osteogenesis, respectively. Together, these results demonstrate for the first time a critical role for Lats1/2 in the maintenance of the granulosa cell genetic program and further highlight the remarkable plasticity of granulosa cells.—Tsoi, M., Morin, M., Rico, C., Johnson, R. L., Paquet, M., Gévry, N., Boerboom, D. Lats1 and Lαts2 are required for ovarian granulosa cell fate maintenance. FASEB J. 33, 10819–10832 (2019). http://www.fasebj.org

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The Hippo pathway in organ development, homeostasis, and regeneration

Cited by 197 publications

References 63 publications

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

Linking YAP to Müller glia quiescence exit in the degenerative retina

Lats1andLats2are required for ovarian granulosa cell fate maintenance

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