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Functional conservation of Nematostella Wnts in canonical and noncanonical Wnt-signaling.

ABSTRACT: Cnidarians surprise by the completeness of Wnt gene subfamilies (11) expressed in an overlapping pattern along the anterior-posterior axis. While the functional conservation of canonical Wnt-signaling components in cnidarian gastrulation and organizer formation is evident, a role of Nematostella Wnts in noncanonical Wnt-signaling has not been shown so far. In Xenopus, noncanonical Wnt-5a/Ror2 and Wnt-11 (PCP) signaling are distinguishable by different morphant phenotypes. They differ in PAPC regulation, cell polarization, cell protrusion formation, and the so far not reported reorientation of the microtubules. Based on these readouts, we investigated the evolutionary conservation of Wnt-11 and Wnt-5a function in rescue experiments with Nematostella orthologs and Xenopus morphants. Our results revealed that NvWnt-5 and -11 exhibited distinct noncanonical Wnt activities by disturbing convergent extension movements. However, NvWnt-5 rescued XWnt-11 and NvWnt-11 specifically XWnt-5a depleted embryos. This unexpected 'inverse' activity suggests that specific structures in Wnt ligands are important for receptor complex recognition in Wnt-signaling. Although we can only speculate on the identity of the underlying recognition motifs, it is likely that these crucial structural features have already been established in the common ancestor of cnidarians and vertebrates and were conserved throughout metazoan evolution.

SUBMITTER: Rigo-Watermeier T

PROVIDER: S-EPMC3507168 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Functional conservation of Nematostella Wnts in canonical and noncanonical Wnt-signaling.

Rigo-Watermeier T T Kraft B B Ritthaler M M Wallkamm V V Holstein T T Wedlich D D

Biology open 20111110 1

Cnidarians surprise by the completeness of Wnt gene subfamilies (11) expressed in an overlapping pattern along the anterior-posterior axis. While the functional conservation of canonical Wnt-signaling components in cnidarian gastrulation and organizer formation is evident, a role of Nematostella Wnts in noncanonical Wnt-signaling has not been shown so far. In Xenopus, noncanonical Wnt-5a/Ror2 and Wnt-11 (PCP) signaling are distinguishable by different morphant phenotypes. They differ in PAPC reg ...[more]

PMID: 23213367

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Project description:Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling-mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth.SignificanceThis work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.

Dataset Information

Functional conservation of Nematostella Wnts in canonical and noncanonical Wnt-signaling.

Publications

Functional conservation of Nematostella Wnts in canonical and noncanonical Wnt-signaling.

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