RLF and Associated Diseases
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Backgrounds of RLF
The relaxin-like factor (RLF) mediates testicular descent in humans. It is a major developmental hormone that is produced predominantly by the Leydig cells and, to a lesser extent, in the theca cells of ovaries. RLF is the product of the insulin-like factor 3 (INSL3) gene, which is a circulating hormone of the relaxin-insulin family that is synthesized in the gonads of mammals and released into the bloodstream. The RLF gene consists of two exons and one intron, with a similar organization to the relaxin and insulin gene. The structure of RLF deduced from the cDNA comprises a leader sequence, followed by a B domain, and a C domain which links the C terminus of the B chain and the N terminus of the A chain. RLF is indeed a secreted hormone in vivo and is preferentially produced in male mammals. RLF is also expressed, probably as a paracrine factor, in the uterine stroma of the marmoset monkey and placental tissues in a variety of different species. In rodents, testicular RLF gene expression is controlled developmentally and up-regulated during puberty.
Fig.1 Localization of the insulin-relaxin family of hormone genes in the human genome. (Ivell, 2002)
Functions of RLF
The members of the relaxin-like hormone family, relaxin and INSL3, also known as RLF or Leydig cell-derived insulin-like factor (LEY-I-L), are implicated in various mechanisms associated with tumor cell growth, differentiation, invasion, and neovascularization. RLF, produced by the Leydig cells, activates the LGR8 receptors in the gubernaculum, resulting in growth changes that facilitate intra-abdominal migration of the testes to the inguinal canal. RLF is related structurally to relaxin and has been demonstrated to bind to the relaxin receptor with moderate affinity. Relaxin is essential for breast development in the pig and breast and nipple development in rodents. In males, RLF regulates testicular descent during fetal life whereas, in adults, it acts as a germ cell survival factor. Thus, it has been suggested that the RLF could play an important role in testicular function and spermatogenesis. The identification of RLF as a necessary component of the physiological mechanism of testicular descent by gene deletion. RLF is a circulating hormone that binds to a specific membrane-bound receptor LGR8. Studies have indicated that RLF binds and activates LGR8 in the gubernaculum to elicit an increase in cAMP production and growth of this ligament. The RLF signal peptide functions as a secretion facilitator of the pro-hormone.
Expression of RLF in Diseases
Female RLF gene knock-out mice display impaired fertility which at least in part, is caused by impaired ovarian-uterine crosstalk that results in a desynchronized estrous cycle. RLF deletion in male mice showed impaired development of the gubernaculum ligament which resulted in undescended testes and infertility, a condition known as cryptorchidism. The targeted destruction of the mouse RLF gene leads to the failure of the development of the gubernaculum during embryogenesis, resulting in bilateral undescended testicles. Deletion of the RLF gene in mice leads to testicular retention and infertility.
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Reference
- Ivell, R.; Bathgate, R.A.D. Reproductive biology of the relaxin-like factor (RLF/INSL3). Biology of reproduction. 2002, 67(3): 699-705.
