Talk:Developmental Signals - Hippo

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Cite this page: Hill, M.A. (2021, April 21) Embryology Developmental Signals - Hippo. Retrieved from


Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta

Defects in development and differentiation of the placenta are associated with various pregnancy disorders such as miscarriage, stillbirth, preeclampsia, and intrauterine growth restriction. However, our knowledge on critical regulators of human placentation is scarce. In the present study, we show that the Hippo signaling-dependent transcriptional coactivator YAP plays a pivotal role in the maintenance of proliferative trophoblasts, the epithelial cells of the placenta. By binding to the transcription factor TEAD4, YAP stimulates expression of genes promoting trophoblast stemness. Additionally, YAP–TEAD4 complexes actively repress genes associated with the differentiated syncytiotrophoblast, the hormone-secreting cell type of the human placenta. Hence, YAP orchestrates a complex developmental program ensuring growth and expansion of the human placenta. we herein show that YAP, the transcriptional coactivator of the Hippo signaling pathway, promotes maintenance of cytotrophoblast progenitors by different genomic mechanisms. Genetic or chemical manipulation of YAP in these cellular models revealed that it stimulates proliferation and expression of cell cycle regulators and stemness-associated genes, but inhibits cell fusion and production of syncytiotrophoblast (STB)-specific proteins, such as hCG and GDF15.

Huang Z, Zhou J, Leung WT, Gober HJ, Pan X, Li C, Li L & Wang L. (2020). The novel role of Hippo-YAP/TAZ in immunity at the mammalian maternal-fetal interface: Opportunities, challenges. Biomed. Pharmacother. , 126, 110061. PMID: 32145593 DOI. The novel role of Hippo-YAP/TAZ in immunity at the mammalian maternal-fetal interface: Opportunities, challenges

Abstract The Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), originally identified as a regulator of tissue generation and tumorigenesis, has been proven to have a pivotal position in immunity. Its multi-faceted roles in regulating immunity cover both intrinsic mechanism of immune cells and the crosstalk with non-immune cells. Survival of the allogeneic embryo in the maternal uterine environment depends on immune tolerance, supported by the highly orchestrated cooperation between decidual immune cells, decidual stromal cells and trophoblasts at the maternal-fetal interface. The abnormal maternal-fetal dialogue is believed to be associated with adverse pregnancy outcomes such as spontaneous pregnancy loss. Recent breakthroughs shed light on the how the Hippo-YAP/TAZ manipulate the decidualization and trophoblast invasion, while further research is needed to integrate and reconcile existing findings of the Hippo-YAP/TAZ in immunity and to extend them at the context of pregnancy. In this review, we summarized the Hippo-YAP/TAZ pathways, detailed the effects of YAP/TAZ on immune cells, and discussed the role of YAP/TAZ at the maternal-fetal interface and the potential of YAP/TAZ on immunity regulation at the context of pregnancy. Given the remarkable effect of therapeutic intervention of YAP/TAZ in cancer and autoimmune diseases, it is worthy to explore the response to YAP/TAZ inhibition in the maternal-fetal immunity. This may provide a new valuable target for therapy of pregnancy loss, or potentially other pregnancy complications. Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

KEYWORDS: Hippo; Immunity; The maternal-fetal interface; YAP/TAZ PMID: 32145593 DOI: 10.1016/j.biopha.2020.110061

Sharma J & Madan P. (2020). Characterisation of the Hippo signalling pathway during bovine preimplantation embryo development. Reprod. Fertil. Dev. , 32, 392-401. PMID: 31718770 DOI.

Characterisation of the Hippo signalling pathway during bovine preimplantation embryo development

Abstract Blastocyst formation is an important milestone during preimplantation embryo development. During murine preimplantation embryogenesis, the Hippo signalling pathway is known to play a significant role in lineage segregation and henceforth the formation of blastocysts. However, the role of this cell signalling pathway during bovine embryogenesis remains unknown. Thus, the aim of the present study was to characterise the Hippo signalling pathway during bovine preimplantation embryo development. mRNA transcripts of Hippo signalling pathway constituents (i.e. crumbs cell polarity complex component 3 (CRB3), mammalian sterile 20-like 1 (MST1), mammalian sterile 20-like 2 (MST2), Yes associated protein 1 (YAP1), transcriptional coactivator with PDZ-binding motif (TAZ)) were observed during all stages of bovine preimplantation embryo development. To evaluate the localisation of Hippo pathway components, bovine embryos at timed stages of development were stained using specific antibodies and observed under a laser confocal microscope. Although MST1/2 proteins were in the cytoplasm during various stages of bovine embryonic development, TAZ and phosphorylated (p-) YAP were detected in the nucleus during the blastocyst stages. Localisation of TAZ and p-YAP proteins was distinct in the bovine compared with mouse model, suggesting that the Hippo signalling pathway is regulated differently in early bovine embryos. PMID: 31718770 DOI: 10.1071/RD18320

Cho YS, Li S, Wang X, Zhu J, Zhuo S, Han Y, Yue T, Yang Y & Jiang J. (2020). CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus. Genes Dev. , 34, 53-71. PMID: 31857346 DOI.

CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus Abstract Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12 recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer. © 2020 Cho et al.; Published by Cold Spring Harbor Laboratory Press. KEYWORDS: CDK7; CRL4; Cul4; DCAF12; Hippo; Taz; Yap; Yki; cancer; organ size PMID: 31857346 DOI: 10.1101/gad.333146.119


Tension-dependent regulation of mammalian Hippo signaling through LIMD1

J Cell Sci. 2018 Mar 2;131(5). pii: jcs214700. doi: 10.1242/jcs.214700.

Ibar C1, Kirichenko E1, Keepers B1, Enners E1, Fleisch K1, Irvine KD2.


Hippo signaling is regulated by biochemical and biomechanical cues that influence the cytoskeleton, but the mechanisms that mediate this have remained unclear. We show that all three mammalian Ajuba family proteins - AJUBA, LIMD1 and WTIP - exhibit tension-dependent localization to adherens junctions, and that both LATS family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization. This localization of Ajuba and LATS family proteins is also influenced by cell density, and by Rho activation. We establish that junctional localization of LATS kinases requires LIMD1, and that LIMD1 is also specifically required for the regulation of LATS kinases and YAP1 by Rho. Our results identify a biomechanical pathway that contributes to regulation of mammalian Hippo signaling, establish that this occurs through tension-dependent LIMD1-mediated recruitment and inhibition of LATS kinases in junctional complexes, and identify roles for this pathway in both Rho-mediated and density-dependent regulation of Hippo signaling. KEYWORDS: Cytoskeleton; Hippo; Junction; LIMD1; Tension; YAP

PMID: 29440237 DOI: 10.1242/jcs.214700

Role of ROCK Signaling in Formation of the Trophectoderm of the Bovine Preimplantation Embryo

Mol Reprod Dev. 2018 Mar 15. doi: 10.1002/mrd.22976.

Negrón-Pérez VM1, Rodrigues LT2, Mingoti GZ2, Hansen PJ1.


Rho-associated coiled-coil containing protein kinases (ROCK1 and ROCK2) are activated by binding to RHO GTPases and phosphorylate a variety of downstream targets including actinomyosin. In the mouse embryo, ROCK signaling acts to promote formation of trophectoderm (TE) and inhibit formation of the inner cell mass (ICM) by polarizing outer cells of the embryo to inactivate Hippo signaling (Kono et al., 2014; Mihajlović and Bruce, 2016). This article is protected by copyright. All rights reserved. KEYWORDS: trophectoderm, ROCK, bovine, blastocyst

PMID: 29542836 DOI: 10.1002/mrd.22976


Curr Top Dev Biol. 2018;128:59-80. doi: 10.1016/bs.ctdb.2017.10.009. Our First Choice: Cellular and Genetic Underpinnings of Trophectoderm Identity and Differentiation in the Mammalian Embryo. Menchero S1, Sainz de Aja J1, Manzanares M2. Author information Abstract The trophectoderm (TE) is the first cell population to appear in the mammalian preimplantation embryo, as the result of the differentiation of totipotent blastomeres located on the outer surface of the late morula. Trophectodermal cells arrange in a monolayer covering the expanding blastocyst and acquire an epithelial phenotype with distinct apicobasal polarity and a basal lamina placed toward the blastocyst interior. During later development through the periimplantation and gastrulation stages, the TE gives rise to extraembryonic membranes and cell types that will eventually form most of the fetal placenta, the specialized organ through which the embryo obtains maternal nourishment necessary for subsequent exponential growth. The specification of the TE is controlled by the combination of morphological cues arising from cell polarity with differential activity of signaling pathways such as Hippo and Notch, and the restriction to outer cells of lineage specifiers such as CDX2. This is possibly the first symmetry-breaking decision undertaken by the uncommitted cells produced by a handful of mitosis divisions from the newly fertilized zygote. Understanding how this cell lineage is specified will therefore provide unique information about development, differentiation, and how the interplay between cellular morphology and signaling and regulatory factors results in a correctly 3D-patterned embryo. KEYWORDS: Blastocyst; Cdx2; Hippo; Notch; Placenta; Preimplantation development; Stem cells; Trophectoderm PMID: 29477171 DOI: 10.1016/bs.ctdb.2017.10.009


Oocyte-expressed yes-associated protein is a key activator of the early zygotic genome in mouse

Cell Res. 2016 Mar;26(3):275-87. doi: 10.1038/cr.2016.20. Epub 2016 Feb 23.

Yu C1, Ji SY1, Dang YJ2, Sha QQ1, Yuan YF3, Zhou JJ1, Yan LY3, Qiao J3, Tang F2, Fan HY1.


In early mammalian embryos, the genome is transcriptionally quiescent until the zygotic genome activation (ZGA) which occurs 2-3 days after fertilization. Despite a long-standing effort, maternal transcription factors regulating this crucial developmental event remain largely elusive. Here, using maternal and paternal mouse models of Yap1 deletion, we show that maternally accumulated yes-associated protein (YAP) in oocyte is essential for ZGA. Maternal Yap1-knockout embryos exhibit a prolonged two-cell stage and develop into the four-cell stage at a much slower pace than the wild-type controls. Transcriptome analyses identify YAP target genes in early blastomeres; two of which, Rpl13 and Rrm2, are required to mediate maternal YAP's effect in conferring developmental competence on preimplantation embryos. Furthermore, the physiological YAP activator, lysophosphatidic acid, can substantially improve early development of wild-type, but not maternal Yap1-knockout embryos in both oviduct and culture. These observations provide insights into the mechanisms of ZGA, and suggest potentials of YAP activators in improving the developmental competence of cultured embryos in assisted human reproduction and animal biotechnology.

PMID 26902285


Par-aPKC-dependent and -independent mechanisms cooperatively control cell polarity, Hippo signaling, and cell positioning in 16-cell stage mouse embryos

Dev Growth Differ. 2015 Oct;57(8):544-56. doi: 10.1111/dgd.12235. Epub 2015 Oct 9.

Hirate Y1, Hirahara S2, Inoue K3, Kiyonari H3,4, Niwa H5,6, Sasaki H1,7.


In preimplantation mouse embryos, the Hippo signaling pathway plays a central role in regulating the fates of the trophectoderm (TE) and the inner cell mass (ICM). In early blastocysts with more than 32 cells, the Par-aPKC system controls polarization of the outer cells along the apicobasal axis, and cell polarity suppresses Hippo signaling. Inactivation of Hippo signaling promotes nuclear accumulation of a coactivator protein, Yap, leading to induction of TE-specific genes. However, whether similar mechanisms operate at earlier stages is not known. Here, we show that slightly different mechanisms operate in 16-cell stage embryos. Similar to 32-cell stage embryos, disruption of the Par-aPKC system activated Hippo signaling and suppressed nuclear Yap and Cdx2 expression in the outer cells. However, unlike 32-cell stage embryos, 16-cell stage embryos with a disrupted Par-aPKC system maintained apical localization of phosphorylated Ezrin/Radixin/Moesin (p-ERM), and the effects on Yap and Cdx2 were weak. Furthermore, normal 16-cell stage embryos often contained apolar cells in the outer position. In these cells, the Hippo pathway was strongly activated and Yap was excluded from the nuclei, thus resembling inner cells. Dissociated blastomeres of 8-cell stage embryos form polar-apolar couplets, which exhibit different levels of nuclear Yap, and the polar cell engulfed the apolar cell. These results suggest that cell polarization at the 16-cell stage is regulated by both Par-aPKC-dependent and -independent mechanisms. Asymmetric cell division is involved in cell polarity control, and cell polarity regulates cell positioning and most likely controls Hippo signaling. © The Authors Development, Growth & Differentiation published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Society of Developmental Biologists. KEYWORDS: Hippo signaling; Par-aPKC; asymmetric cell division; cell polarity; preimplantation embryo

PMID 26450797

PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation

J Cell Biol. 2015 Sep 28;210(7):1185-97. doi: 10.1083/jcb.201503042.

Bessonnard S1, Mesnard D2, Constam DB1.


The first cell differentiation in mammalian embryos segregates polarized trophectoderm cells from an apolar inner cell mass (ICM). This lineage decision is specified in compacted morulae by cell polarization and adhesion acting on the Yes-associated protein in the Hippo signaling pathway, but the regulatory mechanisms are unclear. We show that morula compaction and ICM formation depend on PC7 and the related proprotein convertases (PCs) Furin and Pace4 and that these proteases jointly regulate cell-cell adhesion mediated by E-cadherin processing. We also mapped the spatiotemporal activity profiles of these proteases by live imaging of a transgenic reporter substrate in wild-type and PC mutant embryos. Differential inhibition by a common inhibitor revealed that all three PCs are active in inner and outer cells, but in partially nonoverlapping compartments. E-cadherin processing by multiple PCs emerges as a novel mechanism to modulate cell-cell adhesion and fate allocation. © 2015 Bessonnard et al.

PMID 26416966

Position- and polarity-dependent Hippo signaling regulates cell fates in preimplantation mouse embryos

Semin Cell Dev Biol. 2015 May 15. pii: S1084-9521(15)00100-7. doi: 10.1016/j.semcdb.2015.05.003. [Epub ahead of print]

Sasaki H1.


During the preimplantation stage, mouse embryos establish two cell lineages by the time of early blastocyst formation: the trophectoderm (TE) and the inner cell mass (ICM). Historical models have proposed that the establishment of these two lineages depends on the cell position within the embryo (e.g., the positional model) or cell polarization along the apicobasal axis (e.g., the polarity model). Recent findings have revealed that the Hippo signaling pathway plays a central role in the cell fate-specification process: active and inactive Hippo signaling in the inner and outer cells promote ICM and TE fates, respectively. Intercellular adhesion activates, while apicobasal polarization suppresses Hippo signaling, and a combination of these processes determines the spatially regulated activation of the Hippo pathway in 32-cell-stage embryos. Therefore, there is experimental evidence in favor of both positional and polarity models. At the molecular level, phosphorylation of the Hippo-pathway component angiomotin at adherens junctions (AJs) in the inner (apolar) cells activates the Lats protein kinase and triggers Hippo signaling. In the outer cells, however, cell polarization sequesters Amot from basolateral AJs and suppresses activation of the Hippo pathway. Other mechanisms, including asymmetric cell division and Notch signaling, also play important roles in the regulation of embryonic development. In this review, I discuss how these mechanisms cooperate with the Hippo signaling pathway during cell fate-specification processes. Copyright © 2015 Elsevier Ltd. All rights reserved. KEYWORDS: Cell fate specification; Hippo signaling pathway; Preimplantation mouse embryo; Trophectoderm

PMID 25986053

Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway

Cell Res. 2015 Jun 5. doi: 10.1038/cr.2015.69. [Epub ahead of print]

Li Y1, Zhou H2, Li F2, Chan SW3, Lin Z1, Wei Z4, Yang Z1, Guo F3, Lim CJ3, Xing W2, Shen Y2, Hong W3, Long J2, Zhang M5.


The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.Cell Research advance online publication 5 June 2015; doi: 10.1038/cr.2015.69.

PMID 26045165


Development. 2014 Jul;141(14):2813-24. doi: 10.1242/dev.107276. Epub 2014 Jun 19. Initiation of Hippo signaling is linked to polarity rather than to cell position in the pre-implantation mouse embryo. Anani S1, Bhat S2, Honma-Yamanaka N2, Krawchuk D2, Yamanaka Y3. Author information Abstract In the mouse embryo, asymmetric divisions during the 8-16 cell division generate two cell types, polar and apolar cells, that are allocated to outer and inner positions, respectively. This outer/inner configuration is the first sign of the formation of the first two cell lineages: trophectoderm (TE) and inner cell mass (ICM). Outer polar cells become TE and give rise to the placenta, whereas inner apolar cells become ICM and give rise to the embryo proper and yolk sac. Here, we analyze the frequency of asymmetric divisions during the 8-16 cell division and assess the relationships between cell polarity, cell and nuclear position, and Hippo signaling activation, the pathway that initiates lineage-specific gene expression in 16-cell embryos. Although the frequency of asymmetric divisions varied in each embryo, we found that more than six blastomeres divided asymmetrically in most embryos. Interestingly, many apolar cells in 16-cell embryos were located at outer positions, whereas only one or two apolar cells were located at inner positions. Live imaging analysis showed that outer apolar cells were eventually internalized by surrounding polar cells. Using isolated 8-cell blastomeres, we carefully analyzed the internalization process of apolar cells and found indications of higher cortical tension in apolar cells than in polar cells. Last, we found that apolar cells activate Hippo signaling prior to taking inner positions. Our results suggest that polar and apolar cells have intrinsic differences that establish outer/inner configuration and differentially regulate Hippo signaling to activate lineage-specific gene expression programs. KEYWORDS: 16-cell stage; Asymmetric division; Cell sorting; Inner cell mass (ICM); Live imaging; Mouse; Trophectoderm (TE); YAP (Yes-associated protein) PMID: 24948601 DOI: 10.1242/dev.107276