Dual function of Yap in the regulation of lens progenitor cells and cellular polarity
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Keywords:
Cell fate determination
Cell polarity
Hippo signaling pathway
Progenitor
Hippo signaling pathway
Adherens junction
Cell polarity
Cell fate determination
Inner cell mass
Asymmetric cell division
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The Hippo pathway is a conserved signaling network that regulates organ growth and cell fate. One such cell fate decision is that of R8 photoreceptor cells in the Drosophila eye, where Hippo specifies whether cells sense blue or green light. We show that only a subset of proteins that control organ growth via the Hippo pathway also regulate R8 cell fate choice, including the STRIPAK complex, Tao, Pez, and 14-3-3 proteins. Furthermore, key Hippo pathway proteins were primarily cytoplasmic in R8 cells rather than localized to specific membrane domains, as in cells of growing epithelial organs. Additionally, Warts was the only Hippo pathway protein to be differentially expressed between R8 subtypes, while central Hippo pathway proteins were expressed at dramatically lower levels in adult and pupal eyes than in growing larval eyes. Therefore, we reveal several important differences in Hippo signaling in the contexts of organ growth and cell fate.
Hippo signaling pathway
Cell fate determination
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Summary The canonical function of the Hippo signaling pathway is regulation of organ growth. How this pathway controls cell fate determination is less well understood. Here, we uncover a function of the Hippo pathway in developmental cell fate decisions in the Drosophila eye-antennal disc exerted through the interaction of Yorkie (Yki) with the transcriptional regulator Bonus (Bon), an ortholog of mammalian Transcriptional Intermediary Factor 1/tripartite motif (TIF1/TRIM) family proteins. Instead of controlling tissue growth, Yki and Bon promote epidermal and antennal fates at the expense of the eye fate. Proteomic, transcriptomic, and genetic analyses reveal that Yki and Bon control these cell fate decisions by recruiting transcriptional and post-transcriptional co-regulators, and by activating epidermal differentiation genes and repressing Notch target genes. Our work expands the range of functions and regulatory mechanisms under Hippo pathway control.
Hippo signaling pathway
Cell fate determination
Genetic screen
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Abstract During mammalian development, the challenge for the embryo is to override intrinsic cellular plasticity to drive cells to distinct fates. Here, we unveil novel roles for the HIPPO signaling pathway segregates pluripotent and extraembryonic fates by controlling cell positioning as well as expression of Sox2, the first marker of pluripotency in the mouse early embryo. We show that maternal and zygotic YAP1 and WWTR1 repress Sox2 while promoting expression of the trophectoderm gene Cdx2 in parallel. Yet, Sox2 is more sensitive than Cdx2 to Yap1/Wwtr1 dosage, leading cells to a state of conflicted cell fate when YAP1/WWTR1 activity is moderate. Remarkably, HIPPO signaling activity resolves conflicted cell fate by repositioning cells to the interior of the embryo, independent of its role in regulating Sox2 expression. Rather, HIPPO antagonizes apical localization of Par complex components PARD6B and aPKC. Thus, negative feedback between HIPPO and Par complex components ensure robust lineage segregation.
YAP1
Hippo signaling pathway
Cell fate determination
Inner cell mass
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Loss of cell polarity has been shown to play an essential role in the cause and progression of carcinogenesis in cells of epithelial origin. Three polarity protein systems (PPS) are involved in the acquisition and maintenance of cell polarity: the apical Crumbs complex(Crumbs, Pals1,PatJ), the subapical Par complex(Par6, Par3,aPKC), and the basolateral Scribble complex(Lgl1/2, Dlg1, Scribble). It is now well accepted that the Hippo pathway and its transcriptional co-activators yes-associated protein (YAP)/TAZ (WWTR1) are well connected to PPS via partly unknown mechanisms. In this project we aim to define the crosstalk between PPS complexes formation and activity of the Hippo/YAP pathway.
Hippo signaling pathway
Cell polarity
Crosstalk
Polarity (international relations)
Epithelial polarity
PDZ domain
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Significance The control of organ growth involves cell–cell communication that is mediated by signal transduction pathways. The Hippo signaling pathway has emerged as an essential regulator of organ size in Drosophila and mammals, and defects in Hippo signaling drive cancer progression. An important unresolved question in the growth control field is, How is the Hippo pathway regulated? Recent reports show that adherens junctions and cell polarity complexes regulate the Hippo pathway, but controversy exists about the mechanisms involved. Here we report that in Drosophila and in mammalian cells, adherens junctions and basolateral polarity complexes regulate the Hippo pathway independently of each other. These results thus deepen our knowledge of this important growth control and tumor suppressor pathway.
Adherens junction
Hippo signaling pathway
Cell polarity
Polarity (international relations)
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Hippo signaling pathway
Adherens junction
Cell polarity
Inner cell mass
Cell fate determination
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Citations (398)
During mammalian development, the challenge for the embryo is to override intrinsic cellular plasticity to drive cells to distinct fates. Here, we unveil novel roles for the HIPPO signaling pathway in controlling cell positioning and expression of Sox2, the first marker of pluripotency in the mouse early embryo. We show that maternal and zygotic YAP1 and WWTR1 repress Sox2 while promoting expression of the trophectoderm gene Cdx2 in parallel. Yet, Sox2 is more sensitive than Cdx2 to Yap1/Wwtr1 dosage, leading cells to a state of conflicted cell fate when YAP1/WWTR1 activity is moderate. Remarkably, HIPPO signaling activity resolves conflicted cell fate by repositioning cells to the interior of the embryo, independent of its role in regulating Sox2 expression. Rather, HIPPO antagonizes apical localization of Par complex components PARD6B and aPKC. Thus, negative feedback between HIPPO and Par complex components ensure robust lineage segregation.
YAP1
Hippo signaling pathway
Cell fate determination
Inner cell mass
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Epicardium is the outmost layer of heart and regulates heart development by contributing to the heart tissue and secreting signaling molecules. Epicardial-derived cells, EPDC, is a group of multi-potent cells mainly derive into cardiac fibroblasts and smooth muscle cells. Hippo signaling pathway controls organ growth through regulating cell proliferation. Yap, the effector of Hippo pathway has been shown to regulate mechanosensing and cell fate. However, the function of Hippo signaling in EPDC development has not been studied yet. To study the role of Hippo signaling in development of epicardium and EPDC, we used epicardial specific line, Wt1 CreERT2 , to conditionally delete the components of the pathway, Lats1/2. Cre activity was induced at embryonic day (E)11.5 and Lats1/2 CKO hearts exhibited disorganized coronary vasculature. We used genetic lineage tracing approach to track EPDC and revealed increased endothelial cells deriving from EPDC, suggesting that EPDC changed cell fate. We observed that shape of the epicardial cells became rounded with decreased F-actin in Lats1/2 CKO, which suggested that cell tension was reduced. Since mechanical properties of cellular microenvironment are known to regulate cell shape and influence cell fate determination, we hypothesize that Hippo pathway regulates mechanical property to control cell fate in EPDC. Transcription analysis showed that signals regulating cytoskeleton organization were disrupted, which suggests Hippo regulates cytoskeleton gene expression and affects mechanical force that cell sensed autonomously. Proliferation assay using EdU incorporation showed increased proliferation in EPDC of Lats1/2 CKO was observed, which suggests the changes of external tension cell sensed. To recapitulate the changes of external tension, we plated EPDC onto different stiffness substrate. EPDC of Lats1/2 CKO differentiated into endothelial cells on the soft substrate. On the other hand, Lats1/2 CKO did not derive endothelial cells on the hard substrate and wild type EPDC did not differentiate into endothelial cells on neither soft nor hard substrate. Taken together, our results suggested that Hippo pathway affected EPDC fate determination through controlling internal and external mechanical cues.
Hippo signaling pathway
Cell fate determination
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Hippo signaling pathway
Cell fate determination
Genetic screen
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