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First published online March 5, 2008
doi: 10.1242/10.1242/jcs.026096

Journal of Cell Science 121, 737-746 (2008)
Published by The Company of Biologists 2008
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Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease

Paola Bovolenta1,2,*, Pilar Esteve1,2, Jose Maria Ruiz1,2, Elsa Cisneros1,2 and Javier Lopez-Rios1

1 Departamento de Neurobiología Molecular, Celular y del Desarrollo, Instituto Cajal, CSIC, Dr Arce 37, Madrid 28002, Spain
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Instituto de Salud Carlos III, Madrid, Spain


Figure 1
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  		Fig. 1. Phylogenetic analysis of the SFRP family obtained by comparison of the CRD amino-acid sequences. Members displaying the most similarities in amino acid sequences cluster together and the branch length is proportional to divergence (percentage of nucleotide changes). Numbers indicate the bootstrap confidence for each node (n=1000). Different subfamilies are coloured differently. am, Ambystoma mexicanum (axolotl); c, Gallus gallus (chick); Ce, Caenorhabditis elegans (nematode); ci, Ciona intestinalis (sea squirt); Cr, Crescent; h, Homo sapiens (human); m, Mus musculus (mouse); ol, Oryzias latipes (medaka fish); S, Sfrp; sp, Strongylocentrotus purpuratus (sea urchin); Sz, Sizzled; X, Xenopus laevis (African clawed frog); z, Danio rerio (zebrafish).

 

Figure 2
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  		Fig. 2. Expression of Sfrp1 in the anterior part of the embryo of medaka fish Oryzias latipes (olSfrp1) and chick (cSfrp1). (A-D) Panels show dorsal views of medaka fish (A,C) and chick (B,D) embryos hybridised in toto with digoxigenin-labelled species-specific probes against Sfrp. Gene transcripts accumulate in the most-anterior neural plate (black arrowheads in A) at mid-gastrula stages in both species. In both species expression is particularly abundant in the prospective eye field (orange arrowheads in A and B). In fish, expression is also observed in the future midbrain-hindbrain boundary (black arrowheads in A). During organogenesis (C,D) Sfrp1 expression is observed in the eye, otic vesicles, neural tube, somites and limb buds. hn, Hensen's node; St, embryonic stage, numbers indicate days. Scale bar in D: 50 µm for A, 125 µm for B, 100 µm for C, 500 µm for D.

 

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  		Fig. 3. Possible mechanisms by which SFRPs could modulate Wnt signalling. (A) SFRPs could sequester Wnt either through the CRD or NTR domain, thereby acting as classical antagonists. (B) They could titrate one another's activity, thereby favouring Wnt signalling. (C) SFRPs could act in a dominant-negative fashion by forming signalling-inactive complexes with Fz receptors, thereby preventing signal transduction by Wnt. (D) SFRPs might favour a Wnt-Fz interaction by simultaneously binding to both molecules and promoting signal transduction.

 

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  		Fig. 4. Proposed mechanism of SFRP1 activity as an axon guidance cue. SFRP1 can directly modify and reorient the growth of retinal ganglion cell growth cones. This activity does not require Wnt inhibition and is mediated by Fz2. It requires pertussis-toxin-sensitive activation of Ga protein, involves protein synthesis and degradation, and is modulated by different levels of cAMP and cGMP (Rodriguez et al., 2005Go).

 

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  		Fig. 5. SFRP interactions with molecules unrelated to Wnt signalling. (A) SFRP2 binds to the fibronectin (FN)–integrin-{alpha}5β1 complex, promoting cell adhesion and inhibiting apoptosis. (B) Sizzled binds to and inhibits the activity of BMP1/Tolloid metalloproteinases that cleave chordin, a BMP signalling antagonist. Thus, Sizzled favours chordin stabilisation, which in turn inactivates BMP signalling. (C) SFRP1 interacts with RANKL, preventing it from binding to RANK, and thus inhibits osteoclast formation.

 

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© The Company of Biologists Ltd 2008