Reproductive biology of the relaxin-like factor (RLF/INSL3). Biol Reprod 2002; 67:699–705


The relaxin-like factor (RLF), which is the product of the in-sulin-like factor 3 (INSL3) gene, is a new circulating peptide hormone of the relaxin-insulin family. In male mammals, it is a major secretory product of the testicular Leydig cells, where it appears to be expressed constitutively but in a differentiation-dependent manner. In the adult testis, RLF expression is a good marker for fully differentiated adult-type Leydig cells, but it is only weakly expressed in prepubertal immature Leydig cells or in Leydig cells that have become hypertrophic or transformed. It is also an important product of the fetal Leydig cell popula-tion, where it has been demonstrated using knockout mice to be responsible for the second phase of testicular descent acting on the gubernaculum. INSL3 knockout mice are cryptorchid, and in estrogen-induced cryptorchidism, RLF levels in the testis are significantly reduced. RLF is also made in female tissues, particularly in the follicular theca cells of small antral follicles and in the corpus luteum of the cycle and pregnancy. The ru-minant ovary has a very high level of RLF expression, and anal-ysis of primary cultures of ovarian theca-lutein cells indicated that, as in the testis, expression is probably constitutive but dif-ferentiation dependent. Female INSL3 knockout mice have al-tered estrous cycles, where RLF may be involved in follicle se-lection, an idea strongly supported by observations on bovine secondary follicles. Recently, a novel 7-transmembrane domain receptor (LGR8 or Great) has been tentatively identified as the RLF receptor, and its deletion in mice leads also to cryptorchi-dism. follicular development, Leydig cells, relaxin, theca cell

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