Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization

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Abstract

nt signalling pathways regulate cell proliferation, cell fate and morphogenetic movements. Here, we demonstrate that the Frizzled (Fz) family of Wnt receptors1,2,3,4, similarly to G-protein-coupled receptors (GPCRs)5,6,7, form specific homo- and hetero-oligomers. Two lines of evidence suggest that oligomerization occurs in the endoplasmic reticulum: first, a mutant allele of Fz4, encoding a truncated protein that is retained in the endoplasmic reticulum, is linked to the autosomal-dominant retinal degenerative disease, familial exudative vitreoretinopathy (FEVR)8. We show that this mutant form of Fz4 oligomerizes with wild-type Fz4, retains it in the endoplasmic reticulum and inhibits its signalling. Second, a derivative of Fz1 targeted to the endoplasmic reticulum traps wild-type Fz1 in the endoplasmic reticulum and blocks its signalling. These data support the hypothesis that oligomerization of mutant and wild-type Fz proteins occurs in the endoplasmic reticulum and may explain the genetic dominance of this FEVR allele.

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Figure 1: Fzs homo- and hetero-oligomerize.
Figure 2: The heptahelical domain of Fz is sufficient for oligomerization.
Figure 3: Fzs oligomerize in the endoplasmic reticulum.
Figure 4: Mutant Fz4 inhibits wild-type Fz4.

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Acknowledgements

We thank M. MacDonald and P. Goldberg of Xenon Genetics for the Fz4 constructs, H. Blau of Stanford for the β-Gal complementation constructs and S. Angers for helpful comments. A.K. was supported in part by a National Institutes of Health reproductive biology training grant. R.T.M is an Investigator, and A.K. and J.Y.S. are associates, of the Howard Hughes Medical Institute. M.B. and M.H. were supported in part by the Canadian Institute for Health Research, and M.H. holds a studentship from the Fonds de la recherche en Santé du Québec.

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Correspondence to Randall T. Moon.

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