Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jan;46(1):51-63.
doi: 10.1016/j.tibs.2020.08.008. Epub 2020 Sep 11.

Hippo Signaling in Embryogenesis and Development

Zhengming Wu  1 , Kun-Liang Guan  2
Affiliations
Review

Hippo Signaling in Embryogenesis and Development

Zhengming Wu et al. Trends Biochem Sci. 2021 Jan.

Abstract

Hippo pathway components are structurally and functionally conserved and are notable for their role in controlling organ size. More diverse functions of the Hippo pathway have been recognized, including development, tissue homeostasis, wound healing and regeneration, immunity, and tumorigenesis. During embryogenesis, different signaling pathways are repeatedly and cooperatively activated, leading to differential gene expression in specific developmental contexts. In this article, we present an overview on the regulation and function of the Hippo pathway in mammalian early development. We introduce the Hippo pathway components and major upstream signals that act through this pathway to influence embryogenesis. We also discuss the roles of Hippo pathway in tissue specification and organ development during organogenesis.

Keywords: HIPPO; YAP/TAZ; early development; embryogenesis; stem cells.

PubMed Disclaimer

Conflict of interest statement

Disclosure Statement

K.-L.G. is a co-founder and has equity interest in Vivace Therapeutics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

Figures

Figure 1
Figure 1
The mammalian Hippo pathway and its regulation by cell-cell and cell-matrix contact. MST1/2, MAP4Ks and LATS1/2 kinases are activated by phosphorylation. YAP/TAZ are inhibited by LATS dependent phosphorylation, which promotes YAP/TAZ cytoplasmic localization and degradation. STRIPAK inhibits MST and MAP4Ks by dephosphorylation. ECM acts via integrin to modulate the Hippo pathway. Cell-cell contact signal is detected by adherens junction and tight junction and mediated by AMOT family protein to stimulate Hippo signaling. In the absence of nuclear YAP/TAZ, VGLL4 binds TEAD to repress transcription.
Figure 2.
Figure 2.
Crosstalk of the Hippo pathway with other developmental cues. Stimulation of GPCR can either positively or negatively affect YAP/TAZ activity in a manner dependent on the type of heterotrimeric G proteins coupled to the receptor. Notch intracellular domain (NICD), the effector of NOTCH signaling, enhances YAP/TAZ activity by promoting protein stability. TAZ binds SMAD, the effector of TGF-β signaling, to promote its nuclear translocation. YAP/TAZ are stimulated by Wnt ligands.
Figure 3.
Figure 3.
Functions of Hippo pathway in embryogenesis and development. This diagram shows the YAP/TAZ subcellular distributions and their functions at different embryonic stages. In zygotes, YAP/TAZ is critical in preventing the premature expression of SOX2 and abnormal ICM differentiation. In morula and blastocyst, cells are specialized depending on Hippo pathway activity in response to their position and polarity. The exterior cells with high YAP/TAZ activity develop into trophoblasts while the inner cells with low YAP/TAZ activity develop into ICM. YAP/TAZ is required for organogenesis in all three germ layers. The color of cell outlines and text boxes represent certain germ layers (gray, blue, green, and red for trophectoderm, ectoderm, mesoderm, and endoderm, respectively). The text in colored background denotes phenotypes of altered Hippo signaling at each indicated embryonic “E” stage.
See this image and copyright information in PMC

References

    1. Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ. The Drosophila Tumor-Suppressor Gene Warts Encodes a Homolog of Human Myotonic-Dystrophy Kinase and Is Required for the Control of Cell-Shape and Proliferation. Gene Dev. 1995;9(5):534–46. doi: DOI 10.1101/gad.9.5.534. - DOI - PubMed
    1. Xu TA, Wang WY, Zhang S, Stewart RA, Yu W. Identifying Tumor Suppressors in Genetic Mosaics - the Drosophila Lats Gene Encodes a Putative Protein-Kinase. Development. 1995;121(4):1053–63. - PubMed
    1. Morin-Kensicki EM, Boone BN, Howell M, Stonebraker JR, Teed J, Alb JG, et al. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Molecular and Cellular Biology. 2006;26(1):77–87. doi: 10.1128/Mcb.26.1.77-87.2006. - DOI - PMC - PubMed
    1. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells (vol 17, pg 2054, 2007). Current Biology. 2007;17(23):2094-. doi: 10.1016/j.cub.2007.11.016. - DOI - PubMed
    1. Ma SH, Meng ZP, Chen R, Guan KL. The Hippo Pathway: Biology and Pathophysiology. Annu Rev Biochem. 2019;88:577–604. doi: 10.1146/annurev-biochem-013118-111829. - DOI - PubMed

Publication types

Substances