Identification of a novel PDZ domain containing protein, fzip, as an interacting partner of frizzled

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The frizzled gene family encodes serpentine membrane receptors, which are proposed to be cognate receptors for Wnt molecules. Although Wnt molecules are suggested to regulate several signaling pathways, the precise mechanisms are largely unknown. We initiated the search for frizzled interacting proteins, since no direct downstream molecules for frizzled gene family have been identified in any organisms.By using yeast two-hybrid system, we have identified a novel frizzled interacting protein, fzip-1. Fzip-1 contains two coiled-coil motifs and one PDZ domain which is involved in the binding to the S/T-X-V-COOH motif of frizzled. Interestingly, although fzip-1 is associated with the Golgi apparatus, it translocated to the plasma membrane when frizzled was co-expressed, suggesting that fzip-1 may play a role to translocate frizzled proteins from Golgi apparatus to plasma membrane.Since Wnt signaling pathways are implicated in many aspects of developmental process as well as tumorgenesis, we generated fzip-1 deficient mice by gene targeting. Fzip-1 homozygous mutant mice were viable and exhibited no visible phenotype. However, in breeding experiments, it became apparent that male homozygous mutant mice were consistently infertile. Although no overt abnormality was observed in the initiation of spermatogenesis, most of the spermatozoa in epididymis had aberrant head morphology and lacked acrosome. In spermatids, significant accumulation of fzip-1 was observed in perinuclear regions. Taken together, these results indicate that fzip-1 is required for the vesicle transport from the Golgi apparatus, and that it may play a role in the membrane transport of frizzled.