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First published online September 28, 2005
doi: 10.1242/10.1242/dev.02068

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The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity

¹ Section of Molecular Cell and Developmental Biology, and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712, USA
² Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
³ Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA

View larger version (21K): [in a new window]   Fig. 1. Dishevelled mediates at least three signaling cascades. (A) The canonical WNT pathway. WNT signals are received by a Frizzled (FZ) receptor and a LRP co-receptor. The signal is transduced through Dishevelled and various other proteins, leading eventually to the stabilization of ß-Catenin, which then together with LEF/TCF controls the transcription of target genes. (B) The non-canonical or planar cell polarity (PCP) cascade. A signal is received by a FZ receptor (in Drosophila, no WNT has yet been implicated in PCP signaling in vertebrates, although WNT11 and WNT5a are necessary), and transduced via Dishevelled to RAC and RHO, which then activate downstream targets to modulate the actin cytoskeleton. (C) The WNT/Ca2+ pathway. WNT signaling through the FZ receptors and Dishevelled and G-proteins leads to the release of intracellular calcium and signaling via Phospholipase C, CamK2 and PKC (Miller et al., 1999a; Sheldahl et al., 1999; Sheldahl et al., 2003). Image reproduced with permission from BioMedCentral (see Habas and Dawid, 2005). APC, Adenomatous Polyposis Coli; CKI, Casein kinase 1; CamK2, calcium/calmodulin-dependent kinase 2; GBP, GSK3 Binding Protein; GSK3, Glycogen synthase kinase 3; JNK, Jun kinase; LRP, Low-density lipoprotein receptor-related protein; PKC, Protein kinase C; TCF/LEF, Lymphoid Enhancer-Binding Factor/T-Cell Specific Transcription Factor; ß-TrCP, Beta-Transducin Repeat Containing Protein; ROCK, RHO-associated coiled-coil forming kinase.

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View larger version (107K): [in a new window]   Fig. 2. Alignment of Dishevelled protein sequences from Hydra, honey bee, Drosophila, Ciona, Xenopus and mouse. The DIX domain covers approximately amino acid (aa) 15-90, the PDZ domain covers approximately aa 260-360, and the DEP domain covers approximately aa 460-530. Downstream of the DEP domain, an invariant proline, serine and two glycines can be found. The extreme C-terminal 24 amino acids are also very highly conserved from Hydra (and also in the planarian, not shown) to mouse. Curiously, although well conserved in the honey bee, this region is poorly conserved in published Drosophila DSH sequences, and a cursory BLAST search failed to find a similar sequence in the Drosophila genome.

View larger version (37K): [in a new window]   Fig. 3. Dishevelled-dependent canonical WNT signals govern embryo patterning. (A) Dishevelled is required to maintain segment polarity in Drosophila. A WNT signal (blue) is produced in the posterior of each segment and is received by Frizzled receptors on the anterior-most cell of the neighboring segment. This canonical WNT signal is transduced by Dishevelled. (B) A wild-type Drosophila embryo (top) and an embryo with disrupted canonical Wingless/WNT signaling (bottom). Images courtesy of K. Wharton (University of Texas, Southwestern Medical School). (C) Canonical WNT signals govern both dorsoventral patterning of the mesoderm (orange denotes dorsal; red, ventral) and anteroposterior patterning of the neuroectoderm (light blue denotes anterior; dark blue, posterior). (D) A normal Xenopus embryo (top) and an embryo with a duplicated axis resulting from ectopic ventral activation of canonical WNT signaling (bottom).

View larger version (53K): [in a new window]   Fig. 4. Dishevelled-dependent PCP signaling governs cell polarity. (A) A schematic of planar polarity establishment in the Drosophila wing (a higher magnification view is shown in B). Dishevelled-dependent PCP signaling coordinates the orientation of distally pointing, actin-rich hairs in these cells. The arrangement of these cells remains constant, and long-term cross-talk between neighboring cells is essential for polarity establishment. (C) A schematic of planar polarity during convergent extension in Xenopus (a higher magnification view is shown in D). Convergent extension is driven by polarized cell interdigitation. By crawling between one another along a single axis, the population of cells is converted from being short and wide to long and narrow. Dishevelled-dependent PCP signaling is essential to the stabilization of lamellipodia specifically on the mediolateral faces of these cells. Unlike Drosophila wing cells, these cells are constantly changing neighbours. How the PCP signaling cascade has changed to accommodate this dynamic situation is a topic of great interest. (E) Wing hairs on a normal Drosophila embryo all point distally, but such polarity is perturbed in an embryo with disrupted Dishevelled signaling (images courtesy of Jeff Axelrod, Stanford University School of Medicine). (F) Xenopus mesoderm cells engaged in convergent extension are aligned and polarized, but this polarity is perturbed in an embryo with disrupted Dishevelled signaling.

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