Edited by: Andrea Erika Münsterberg, University of East Anglia, United Kingdom
Reviewed by: Christine Hartmann, University of Münster, Germany; Victoria Sherwood, University of Dundee, United Kingdom
*Correspondence: Marc Gentzel
This article was submitted to Signaling, a section of the journal Frontiers in Cell and Developmental Biology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dishevelled (DVL) proteins are highly conserved in the animal kingdom and are important key players in β-Catenin-dependent and -independent Wnt signaling pathways. Vertebrate genomes typically comprise three DVL genes, DVL1, DVL2, and DVL3. Expression patterns and developmental functions of the three vertebrate DVL proteins however, are only partially redundant in any given species. Moreover, expression and function of DVL isoforms have diverged between different vertebrate species. All DVL proteins share basic functionality in Wnt signal transduction. Additional, paralog-specific interactions and functions combined with context-dependent availability of DVL isoforms may play a central role in defining Wnt signaling specificity and add selectivity toward distinct downstream pathways. In this review, we recapitulate briefly cellular functions of DVL paralogs, their role in vertebrate embryonic development and congenital disease.
The Dishevelled (dsh1) phenotype has been described the first time in Drosophila close to 60 years ago (Fahmy and Fahmy,
DVL and its core functions in β-Catenin-dependent and -independent Wnt pathways are highly conserved. Notably, the genomes of Drosophila and most other invertebrates harbor only a single
All DVL proteins share an N-terminal DIX domain, a PDZ and a DEP domain (Axelrod et al.,
DVL interacts with the cytoplasmic interface of Frizzled receptors (Tauriello et al.,
Notably, for most of the abovementioned DVL functions no preference for a DVL paralog has been detected, although some studies suggest dose-dependent effects (e.g., Cervenka et al.,
In early
In chicken embryos, only two
All murine
Phylogenetic analyses suggest that
Both, animal models and human congenital disease provide insights into the developmental function of vertebrate DVL paralogs. To date, DVL has predominantly been studied in the mouse and, to a much lesser extent, in
During embryonic development, the neural tube is formed by elevation, convergence and fusion of the lateral neural folds to form a hollow tube. Morphogenesis and closure of the neural tube is affected by nutritional, environmental and genetic factors including Wnt/PCP signaling, which is illustrated by genetic association between NTD in humans and mutations in the PCP genes
Consistently, neural tube closure also requires the same PCP factors in mouse, frog, and zebrafish (Darken et al.,
Robinow syndrome is a rare genetic disorder characterized by mesomelic limb shortening, short stature, cranio-facial malformations, microgenitalia, and occasional cardiac outflow tract defects with either autosomal dominant or recessive inheritance (reviewed in Robinow et al.,
Short stature and defects of the axial skeleton are likely related to impaired convergent extension movements of the paraxial mesoderm and defects in somitogenesis, which have also been reported for DVL2−/−, DVL1−/−;DVL2−/−, and DVL2+/−;DVL3−/− mice as well as for
The characteristic cranio-facial deformations seen in ADRS or RRS indicate defective development of the neural crest (NC), which gives rise to the majority of cranial cartilage and bone. In addition, a subpopulation of the NC contributes to the cardiac outflow tract (OFT). Cranio-facial malformations are also visible in DVL1 and DVL2 morphant
Interestingly,
The recently characterized mutations in
Malformations of the axial skeleton seen in DVL2−/− and DVL1−/−;DVL2−/− mice are reminiscent of the phenotypes in ROR2 or WNT5A deficient embryos that can be attributed to aberrant PCP signaling in the paraxial mesoderm (reviewed in Stricker et al.,
Wnt/β-Catenin signaling also contributes to the development of the paraxial mesoderm, heart and neural crest, and patterns the neural tube. However, defective Wnt/β-Catenin signaling results in patterning defects of the dorsal mesoderm and affects proliferation, expansion, or specification of dorsal neural tube progenitors and neural crest (NC) cells (Greco et al.,
Overall it appears that DVL function in β-Catenin-independent Wnt signaling is more sensitive to the loss or dysfunction of one or two paralogs and accounts for most of the developmental phenotypes in knock-out animal models and also for the features of ADRS.
A number of studies indicate a specific role of DVL1 in cardiac remodeling and regeneration. DVL1 and CamKII are upregulated after induced myocardial infarction and heart failure indicating a role of Wnt/Ca2+ signaling in regeneration (Chen et al.,
Striking differences between different DVLs and species have been observed in temporal and spatial expression patterns. Loss-of-function phenotypes of each single paralog in mouse as well as ADRS features associated with
Functional redundancies however, do not connote biochemical identity. The observed differences could reflect differential expression levels, epistatic relations, or differential biochemical properties such as protein-protein interaction affinity and consequently also molecular function, which would also be consistent with dose-dependencies. The developmental phenotypes further indicate that β-Catenin independent Wnt pathways are more sensitive to the dose of individual DVL paralogs than β-Catenin signaling. This hypothesis is further supported by comparison of triple knock-out and triple-RNAi knock-down embryos. Whereas, in triple KO embryos early β-Catenin signaling is strongly reduced resulting in axis and mesodermal mispatterning, in the knock-down, in which ~25–30% of each paralog were retained, early β-Catenin signaling was not affected, but the embryos showed strong morphogenetic defects in the dorsal mesoderm and neuroectoderm. Consistently, specific and different molecular functionality of the three DVL paralogs has been observed in ciliogenesis and the Wnt/Ca2+ pathway, which were revealed in intact tissue or tissue models (Park et al.,
Overall, the currently available data indicate that DVL expression and function have diverged to some degree apparently and consistent with phylogenetic models mostly between DVL1 and DVL2/3. Thus, depending on the cellular context, DVL paralogs exhibit both redundant and distinct functionality.
All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors' original work was funded by German Research foundation (DFG) grants to AS (grant numbers SCHA965/6-1 and 6-2), MG was funded by the Max Planck Society (MPG).
The Supplementary Material for this article can be found online at: