Beyond the LGR family, splice variants containing only the extracellular region of receptors have also been reported for other GPCRs that have a large ectodomain, such as corticotropin-releasing hormone receptor, metabotropic glutamate receptors and gamma-aminobutyric acid B receptor. In the majority of these cases, the truncated proteins seem to act as molecules that are able to bind but are unable to bring about signaling; this allows fine-tuning of the full-length receptor signals. Lgr4 has been reported to bind R-spondins or BAY 73-4506 norrin; thereby, the forming complex can further enhance the Wnt signaling. Using reporter assays, we demonstrated that the recombinant Lgr4-ED can indeed dampen the Wnt/b-catenin signaling in vitro. Interestingly, balance of the Wnt/b-catenin signaling has been demonstrated to be crucial for normal development of the male and female reproductive systems. For examples, deficiency in the Wnt signaling, including in Wnt4, Wnt5a, and Wnt7a, will result in severe malformation of the TWS119 genitals and infertility, whereas hyperactivation of the Wnt/b-catenin pathway can also lead to germ cell apoptosis and male infertility. Thus, the endogenous expression of Lgr4-ED may act as a decoy molecule that aids modulation of the strength of the Wnt/bcatenin signaling in order to maintain appropriate development conditions for the gonads. Lgr4-null mice show strong dilation of the rete testis and efferent ducts due to defects in liquid reabsorption. These phenotypes are accompanied by down-regulation of steroid receptors, water transporters and ion transporters, including estrogen receptor, androgen receptor, aquaporin 1, aquaporin 9, -ATPase and sodium/hydrogen exchanger 3. Of interest, not only showing the antagonizing effect against the Wnt/b-catenin signaling in vitro, injection of the recombinant Lgr4-ED into mice can also down-regulate the expression of Esr1 and Aqp1 in the testis in vivo.Although there is still no consensus regarding the testicular expression and localization of Esr1 in different species and previous studies on Lgr4-null mice also indicated the reduction of Esr1 immunostaining was mainly observed in the epididymis and efferent ducts but not in the testis, several recent reports have clearly demonstrated that both mRNA and corresponding protein of Esr1 can be detected in the Sertoli cells in mouse and rat testes.