Dishevelled Paralogs in Vertebrate Development: Redundant or Distinct?

Abstract

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.

Keywords: Dishevelled; Wnt signaling; autosomal dominant robinow syndrome; embryonic expression; vertebrate embryonic development.

Figure 1

Dishevelled in Wnt/Frizzled signaling. (A) DVL relays Wnt/Frizzled signals to multiple signaling pathways to regulate cellular functions including mitosis, transcription, polarity, and migration. (B) Heatmap representation of the conservation of all three DVL proteins in human, rat, mouse, and frog. Sequence alignments were calculated using Clustal Omega with the following input sequences: Homo sapiens DVL1: O14640, DVL2: O14641, DVL3: Q92997, Rattus norvegicus DVL1: Q9WVB9, DVL2: D3ZB71, DVL3: D4ADV8, Mus musculus DVL1: P51141, DVL2: Q60838, DVL3: Q61062, Xenopus laevis DVL2: P51142, DVL3: Q6DKE2 (Uniprot Accession numbers), Xenopus laevis DVL1: NCBI XP_018081523. Red indicates 100% identity and Green indicates no identity of amino acids at the respective position. Conservation scores were calculated according to Livingstone and Barton (1993). Functional domains or motifs are indicated by correspondingly labeled boxes; for details and references see text.

Figure 2

Mutations identified in the three DVL genes in humans. Mutations are indicated at the positions of amino acid changes. Changes detected in individuals with NTDs (De Marco et al., ; Merello et al., ; Chen et al., 2016) are color coded orange (predicted pathogenic) and gray (predicted benign, in all cases A>V). All ADRS mutations are (−1)-frameshift mutations resulting in altered amino acid sequences in the C-terminus and a premature stop (Bunn et al., ; White et al., 2015, 2016), which are indicated by hatched area and red line respectively. Positions of individual mutations associated with ADRS are labelled with red dots.