Wnt Signaling in Tissue Differentiation
6 and Morphogenesis
Stefan Hoppler and Michael Kühl
CONTENTS
6.1. Historical Background ................................................................................................................................................. 65
6.2. Characterizing the Wnt Signaling Pathways ................................................................................................................ 65
6.2.1. Canonical Wnt Signaling ................................................................................................................................ 66
6.2.2. Non-Canonical Wnt Signaling ........................................................................................................................ 68
6.2.3. Integration of Canonical and Non-Canonical Wnt Signaling ......................................................................... 68
6.2.4. Integrated Understanding of Wnt Signaling in Vertebrate Embryonic Development ..................................... 69
6.3. Recent Advances .......................................................................................................................................................... 69
6.3.1. Wnt Signaling in Cardiac Organogenesis ....................................................................................................... 69
6.3.2. Modeling Wnt Signaling ................................................................................................................................. 69
6.3.3. Context-Specif c Wnt Signaling ...................................................................................................................... 70
6.4. Future Directions and Important Questions ................................................................................................................. 71
6.4.1. Wnt Interactions with Other Signaling Pathways ........................................................................................... 71
6.4.2. Regulation of Gene Expression by Non-Canonical Wnt Signaling ................................................................ 71
6.4.3. Integration of Wnt Signaling into the Embryonic Signaling and Regulatory Environment ........................... 71
6.4.4. Xenopus as a Model for Human Disease ........................................................................................................ 71
Acknowledgments .................................................................................................................................................................. 72
References .............................................................................................................................................................................. 72
6.1. HISTORICAL BACKGROUND
receptors primarily of the Frizzled family of seven transmembrane receptors. Co-receptors, such as LRP5/6, are also
The Xenopus experimental model system has been instrumen- involved in some signaling contexts (Hoppler and Nakamura,
tal for key discoveries about Wnt signaling in vertebrates, both 2014). Several members of tyrosine kinase receptors also
biochemical mechanisms and developmental functions. Study of have been linked to Wnt signaling such as Ryk, Ror, Ptk7,
Wnt function in dorsal axis establishment, morphogenetic move- and MuSK (Roy et al., 2018).
ments during gastrulation, and neural development provided
Following the independent co-discovery of Wnt genes
insights into Wnt pathway mechanisms inside and between cells. in mouse (int-1, Nusse and Varmus, 1982 ) and Drosophila
Wnt signaling research continues to make important discoveries (wingless, Baker, 1987 ), injection of mRNA coding for
using the Xenopus system (see Sections 3 and 4 ).
Int-1 into early Xenopus embryos demonstrated that Wnt
The success of Xenopus as a model system is explained by proteins also function in vertebrate development; this
it being at the crossroads of different disciplines, as indicated caused a dramatic axis duplication ( McMahon and Moon,
by different techniques and complementary experimental 1989 ). This fundamental experiment became established
approaches, such as: stem-cell/organoid-like embryonic as an important assay for investigating Wnt signaling. Wnt
explants or the ability to perform transplantation experiments pathway activity was subsequently shown to be required for
(for embryology), microscopy analysis (for cell biology), normal axis development (e.g. Heasman et al., 2000 ), and
or extracting lysates in large amounts (for biochemistry). again it was Xenopus that was used as the model system
These unique experimental advantages of the Xenopus model of choice. However, the originally proposed requirement
system have served Wnt signaling research immensely and for endogenous Wnt ligand and receptor function ( Kofron
widely.
et al., 2007 ; Tao et al., 2005 ) has recently been challenged
( Yan et al., 2018 ).
Using the axis duplication assay, Wnt signals were
6.2. CHARACTERIZING THE WNT SIGNALING
subdivided into different classes. Members of the Wnt1
PATHWAYS
class resulted in formation of secondary axis upon mRNA
Wnt glycoproteins are secreted extracellular signal proteins injection into early Xenopus embryos. In addition, they
that initiate intracellular signal transduction by binding to triggered transformation of C57MG mouse mammary
DOI: 10.1201/9781003050230-7
65