Cryptorchidism, or undescended testis, is one of the most common congenital defect in newborn boys. If left untreated, this condition causes infertility and drastically increases the chance of testicular cancer in adulthood. The key aim of this project is to establish the precise network of genetic and biochemical events underlying testicular descent during development. The proposal is based on recent identification of the testicular hormone Insulin-like 3, and its receptor, GREAT, as the critical regulators of gubernacular differentiation. Using mouse crsp mutant we have identified the GREAT gene, showed that it encodes a G protein-coupled receptor, and demonstrated that GREAT is the only cognate receptor for INSL3 in vivo. Mutation analysis of the two genes in cryptorchid patients revealed functionally deleterious mutations, which may be responsible for the abnormal phenotype. A series of transgenic mouse mutants produced in our laboratory provides a unique basis to address specific questions regarding the role and mechanisms of INSL3 signaling in vivo. Furthermore, the fact, that the INSL3 receptor is a GPCR, makes it an attractive target for future therapeutic development. We are going to explore the hypothesis, that INSL3 signaling pathway is a key regulator of testicular descent. To test this hypothesis we propose the following Specific Aims 1: To identify genetic factors leading to the activation of INSL3/GREAT expression during development; 2. To identify downstream target genes controlled by INSL3; 3. To identify cellular pathways involved in INSL3/GREAT signaling; 4. To determine mechanisms of GREAT receptor activation and its desensitization. As a result, we will identify a sequence of genetic events leading to testicular descent and characterize the mechanisms of INSL3/GREAT cellular signaling. The proposed studies will provide a better understanding of the testicular descent and its regulation during male development. ? ?
| Kaftanovskaya, Elena M; Neukirchner, Giselle; Huff, Vicki et al. (2013) Left-sided cryptorchidism in mice with Wilms' tumour 1 gene deletion in gubernaculum testis. J Pathol 230:39-47 |
| Huang, Zaohua; Kaftanovskaya, Elena M; Rivas, Bryan et al. (2013) Mechanisms of INSL3 signaling in male reproductive organs. Ital J Anat Embryol 118:32-3 |
| Agoulnik, Alexander I; Huang, Zaohua; Ferguson, Lydia (2012) Spermatogenesis in cryptorchidism. Methods Mol Biol 825:127-47 |
| Segal, Mark S; Sautina, Laura; Li, Shiyu et al. (2012) Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice. Blood 119:629-36 |
| Kaftanovskaya, Elena M; Huang, Zaohua; Barbara, Agustin M et al. (2012) Cryptorchidism in mice with an androgen receptor ablation in gubernaculum testis. Mol Endocrinol 26:598-607 |
| Huang, Zaohua; Rivas, Bryan; Agoulnik, Alexander I (2012) Insulin-like 3 signaling is important for testicular descent but dispensable for spermatogenesis and germ cell survival in adult mice. Biol Reprod 87:143 |
| Kaftanovskaya, Elena M; Feng, Shu; Huang, Zaohua et al. (2011) Suppression of insulin-like3 receptor reveals the role of ýý-catenin and Notch signaling in gubernaculum development. Mol Endocrinol 25:170-83 |
| Li, Zhen; Feng, Shu; Lopez, Vanessa et al. (2011) Uterine cysts in female mice deficient for caveolin-1 and insulin-like 3 receptor RXFP2. Endocrinology 152:2474-82 |
| Harris, Rebecca M; Finlayson, Courtney; Weiss, Jeffrey et al. (2010) A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism. Mamm Genome 21:442-9 |
| Pepe, Anastasia; Ferlin, Alberto; Gianesello, Lisa et al. (2009) INSL3 plays a role in the balance between bone formation and resorption. Ann N Y Acad Sci 1160:219-20 |
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