title: GREAT/LGR8 is the only receptor for insulin-like 3 peptide.
abstract: During male development testes descend from their embryonic intraabdominal position into the scrotum. Two genes, encoding the insulin-like 3 peptide (INSL3) and the GREAT/LGR8 G protein-coupled receptor, control the differentiation of gubernaculum, the caudal genitoinguinal ligament critical for testicular descent. It was established that the INSL3 peptide activates GREAT/LGR8 receptor in vitro. Mutations of Insl3 or Great cause cryptorchidism (undescended testes) in mice. Overexpression of the transgenic Insl3 causes male-like gubernaculum differentiation, ovarian descent into lower abdominal position, and reduced fertility in females. To address the question whether Great deletion complements the mutant female phenotype caused by the Insl3 overexpression, we have produced Insl3 transgenic mice deficient for Great. Such females had a wild-type phenotype, demonstrating that Great was the only cognate receptor for Insl3 in vivo. We have established that pancreatic HIT cells, transfected with the INSL3 cDNA, produce functionally active peptide. Analysis of five INSL3 mutant variants detected in cryptorchid patients showed that P49S substitution renders functionally compromised peptide. Therefore, mutations in INSL3 might contribute to the etiology of cryptorchidism. We have also showed that synthetic insulin-like peptides (INSL4 and INSL6) were unable to activate LGR7 or GREAT/LGR8.
authors.affiliation: Department of Obstetrics and Gynecology, 6550 Fannin Street, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogatcheva
authors.forename: Anne
authors.initials: A
authors.lastname: Truong
authors.forename: Shu
authors.initials: S
authors.lastname: Feng
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Engel
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Adham
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Agoulnik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003456:Cryptorchidism / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D007328:Insulin; D008098:Litter Size; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011247:Pregnancy; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013552:Swine
chemical_list: D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C435187:relaxin receptor 2, mouse; C033395:relaxin receptors