FZD4S, a splicing variant of frizzled-4 encodes a soluble-type positive regulator of the WNT signaling pathway

Frizzled-1 (FZD1)-FZD10 are seven-transmembrane-type WNT receptors, and SFR P1-SFRPS are soluble-type WNT antagonists. These molecules are encoded by m utually distinct genes. We have previously isolated and characterized the 7 .7-kb FZD4 mRNA, encoding a seven-transmembrane receptor with the extracell ular cysteine-rich domain (CRD), Here, we have cloned and characterized FZD 4S, a splicing variant of the FZD4 gene. FZD4S, corresponding to the 10.0-k b FZD4 mRNA, consisted of exon 1, intron 1, and exon 2 of the FZD4 gene. FZ D4S encoded a soluble-type polypeptide with the N-terminal part of CRD, and was expressed in human fetal kidney. Injection of synthetic FZD4S mRNA int o the ventral marginal zone of Xenopus embryos at the 4-cell stage did not induce axis duplication by itself, but augmented the axis duplication poten tial of coinjected Xwnt-8 mRNA These results indicate that the FZD1 gene gi ves rise to soluble-type FZD4S as well as seven-transmembrane-type FZD4 due to alternative splicing, and strongly suggest that FZD4S plays a role as a positive regulator of the WNT signaling pathway. (C) 2001 Academic Press.