Hippo pathway and Bonus control developmental cell fate decisions in the Drosophila eye

AbstractThe Hippo pathway controls organ growth, however its role in cell fate determination and the underlying mechanism is not well understood. Here, we uncover the function of the Hippo pathway in developmental cell fate decisions in the Drosophila eye, exerted through the interaction of Yorkie (Yki) with a transcriptional regulator Bonus (Bon). Activation of either Bon or Yki is sufficient to promote epidermal fate at the expense of eye fate through the recruitment of multiple transcriptional and post-transcriptional regulators. Transcriptome analysis reveals that Bon and Yki jointly upregulate epidermal differentiation genes and downregulate Notch target genes that modulate the eye-to-epidermal fate switch. The Hippo pathway and Bon also control the early eye-antennal specification, with activated Yki and Bon suppressing eye fate and promoting antennal fate. Our work has revealed that the Hippo pathway and Bon control cell fate decisions during Drosophila eye development at multiple levels.

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The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

10.1101/2020.05.03.075085 ◽

2020 ◽

Cited By ~ 1

Author(s):

Emma Carley ◽

Rachel K. Stewart ◽

Abigail Zieman ◽

Iman Jalilian ◽

Diane. E. King ◽

...

Keyword(s):

Cell Fate ◽

Control Cell ◽

Nuclear Lamina ◽

Epidermal Differentiation ◽

Keratinocyte Differentiation ◽

Linc Complex ◽

Force Transmission ◽

Cell Fate Decisions

AbstractWhile the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

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Control of cellular responses to mechanical cues through YAP/TAZ regulation

Journal of Biological Chemistry ◽

10.1074/jbc.rev119.007963 ◽

2019 ◽

Vol 294 (46) ◽

pp. 17693-17706 ◽

Cited By ~ 30

Author(s):

Ishani Dasgupta ◽

Dannel McCollum

Keyword(s):

Cell Fate ◽

Wound Repair ◽

Hippo Pathway ◽

Three Dimensional ◽

Focal Adhesions ◽

Mechanical Stimuli ◽

Cell Contractility ◽

Cell Fate Decisions ◽

Disease States ◽

The Hippo Pathway

To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.

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A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa052 ◽

2020 ◽

Vol 26 (9) ◽

pp. 653-664

Author(s):

Challis Karasek ◽

Mohamed Ashry ◽

Chad S Driscoll ◽

Jason G Knott

Keyword(s):

Signaling Pathway ◽

Cell Fate ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Cell Mass ◽

Preimplantation Embryos ◽

Hippo Signaling ◽

Cell Fate Decisions ◽

Hippo Signaling Pathway ◽

The Hippo Pathway

Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

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PIASγ controls stability and facilitates SUMO-2 conjugation to CoREST family of transcriptional co-repressors

Biochemical Journal ◽

10.1042/bcj20170983 ◽

2018 ◽

Vol 475 (8) ◽

pp. 1441-1454

Author(s):

Julián Esteban Sáez ◽

Cristian Arredondo ◽

Carlos Rivera ◽

María Estela Andrés

Keyword(s):

Cell Fate ◽

Target Genes ◽

Protein Complexes ◽

Control Cell ◽

E3 Ligase ◽

Cell Fate Determination ◽

Fate Determination ◽

Sumo Protease ◽

Protein Levels ◽

The Stability

CoREST family of transcriptional co-repressors regulates gene expression and cell fate determination during development. CoREST co-repressors recruit with different affinity the histone demethylase LSD1 (KDM1A) and the deacetylases HDAC1/2 to repress with variable strength the expression of target genes. CoREST protein levels are differentially regulated during cell fate determination and in mature tissues. However, regulatory mechanisms of CoREST co-repressors at the protein level have not been studied. Here, we report that CoREST (CoREST1, RCOR1) and its homologs CoREST2 (RCOR2) and CoREST3 (RCOR3) interact with PIASγ (protein inhibitor of activated STAT), a SUMO (small ubiquitin-like modifier)-E3-ligase. PIASγ increases the stability of CoREST proteins and facilitates their SUMOylation by SUMO-2. Interestingly, the SUMO-conjugating enzyme, Ubc9 also facilitates the SUMOylation of CoREST proteins. However, it does not change their protein levels. Specificity was shown using the null enzymatic form of PIASγ (PIASγ-C342A) and the SUMO protease SENP-1, which reversed SUMOylation and the increment of CoREST protein levels induced by PIASγ. The major SUMO acceptor lysines are different and are localized in nonconserved sequences among CoREST proteins. SUMOylation-deficient CoREST1 and CoREST3 mutants maintain a similar interaction profile with LSD1 and HDAC1/2, and consequently maintain similar repressor capacity compared with wild-type counterparts. In conclusion, CoREST co-repressors form protein complexes with PIASγ, which acts both as SUMO E3-ligase and as a protein stabilizer for CoREST proteins. This novel regulation of CoREST by PIASγ interaction and SUMOylation may serve to control cell fate determination during development.

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The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

Cell Death and Disease ◽

10.1038/s41419-021-03409-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anke Hermann ◽

Guangming Wu ◽

Pavel I. Nedvetsky ◽

Viktoria C. Brücher ◽

Charlotte Egbring ◽

...

Keyword(s):

Embryonic Development ◽

Cell Fate ◽

Target Genes ◽

Hippo Pathway ◽

Growth Control ◽

Binding Motif ◽

Hippo Signaling ◽

Large Tumor ◽

Organ Growth ◽

The Hippo Pathway

AbstractThe WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina. In summary, our data elucidate a novel role for Wwc2 as a key regulator in early embryonic development and sprouting angiogenesis in mice.

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The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

10.1101/835454 ◽

2019 ◽

Author(s):

Xiaomeng Zhang ◽

Lie Yang ◽

Pacman Szeto ◽

Youfang Zhang ◽

Kaushalya Amarasinghe ◽

...

Keyword(s):

Cell Fate ◽

Melanoma Cell ◽

Cell Invasion ◽

Molecular Mechanisms ◽

Target Genes ◽

Expression Profiles ◽

Hippo Pathway ◽

Melanoma Metastasis ◽

The Hippo Pathway

ABSTRACTMelanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared to most other skin cancers, a feature of melanoma is its high metastatic capacity, although molecular mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of pathway activity in melanoma cells. Hippo-mediated transcriptional activity varied in melanoma cell lines but failed to cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutation status. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness. Consistent with this, the central Hippo oncogene, YAP, was both necessary and sufficient for melanoma cell invasion in vitro. In in vivo murine studies, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that the Hippo pathway is a critical regulator of melanoma metastasis.

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CDK12 is Necessary to Promote Epidermal Differentiation through Transcription Elongation

10.1101/2021.06.01.446524 ◽

2021 ◽

Author(s):

George Sen ◽

Jingting Li ◽

Manisha Tiwari ◽

Yifang Chen

Keyword(s):

Transcription Factors ◽

Rna Polymerase Ii ◽

Cell Fate ◽

Target Genes ◽

Skin Diseases ◽

Transcription Elongation ◽

The Body ◽

Epidermal Differentiation ◽

Transcription Control ◽

Cell Fate Decisions

Proper differentiation of the epidermis is essential to prevent water loss and to protect the body from the outside environment. Perturbations in this process can lead to a variety of skin diseases that impacts 1 in 5 people. While transcription factors that control epidermal differentiation have been well characterized, other aspects of transcription control such as elongation are poorly understood. Here we show that of the two cyclin dependent kinases (CDK12 and CDK13), that are known to regulate transcription elongation, only CDK12 is necessary for epidermal differentiation. Depletion of CDK12 led to loss of differentiation gene expression and absence of skin barrier formation in regenerated human epidermis. CDK12 binds to genes that code for differentiation promoting transcription factors (GRHL3, KLF4, and OVOL1) and is necessary for their elongation. CDK12 is necessary for elongation by promoting Ser2 phosphorylation on the C-terminal domain of RNA polymerase II and the binding of the elongation factor SPT6 to target genes. Our results suggest that control of transcription elongation by CDK12 plays a prominent role in adult cell fate decisions.

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Pits and CtBP control tissue growth in Drosophila melanogaster with the Hippo pathway transcription repressor, Tgi

10.1101/847707 ◽

2019 ◽

Author(s):

Joseph H.A. Vissers ◽

Lucas G. Dent ◽

Colin House ◽

Shu Kondo ◽

Kieran F. Harvey

Keyword(s):

Cell Fate ◽

Transcriptional Repression ◽

Target Genes ◽

Affinity Purification ◽

Hippo Pathway ◽

Transcriptional Response ◽

Size Control ◽

Tissue Growth ◽

Organ Size ◽

The Hippo Pathway

ABSTRACTThe Hippo pathway is an evolutionary conserved signalling network that regulates organ size, cell fate control and tumorigenesis. In the context of organ size control, the pathway incorporates a large variety of cellular cues such as cell polarity and adhesion into an integrated transcriptional response. The central Hippo signalling effector is the transcriptional co-activator Yorkie, which controls gene expression in partnership with different transcription factors, most notably Scalloped. When it is not activated by Yorkie, Scalloped can act as a repressor of transcription, at least in part due to its interaction with the corepressor protein Tgi. The mechanism by which Tgi represses transcription is incompletely understood and therefore we sought to identify proteins that potentially operate together with it. Using an affinity purification and mass-spectrometry approach we identified Pits and CtBP as Tgi-interacting proteins, both of which have been linked to transcriptional repression. Both Pits and CtBP were required for Tgi to suppress the growth of the D. melanogaster eye and CtBP loss suppressed the undergrowth of yorkie mutant eye tissue. Furthermore, as reported previously for Tgi, overexpression of Pits suppressed transcription of Hippo pathway target genes. These findings suggest that Tgi might operate together with Pits and CtBP to repress transcription of genes that normally promote tissue growth. The human orthologues of Tgi, CtBP and Pits (VGLL4, CTBP2 and IRF2BP2) physically and functionally interact to control transcription, implying that the mechanism by which these proteins control transcriptional repression is conserved throughout evolution.

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The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

eLife ◽

10.7554/elife.58541 ◽

2021 ◽

Vol 10 ◽

Author(s):

Emma Carley ◽

Rachel Stewart ◽

Abigail G Zieman ◽

Iman Jalilian ◽

Diane E King ◽

...

Keyword(s):

Cell Fate ◽

Control Cell ◽

Nuclear Lamina ◽

Epidermal Differentiation ◽

Keratinocyte Differentiation ◽

Linc Complex ◽

Force Transmission ◽

Cell Fate Decisions

While the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

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