GREAT/LGR8 is the only receptor for insulin-like 3 peptide
GREAT/LGR8 is the only receptor for insulin-like 3 peptide
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DOI：
10.1210/me.2003-0096
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发表时间：
2003-12-01
影响因子：
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通讯作者：
Agoulnik, AI
中科院分区：
文献类型：
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作者：
Bogatcheva, NV;Truong, A;Agoulnik, AI
在男性发育过程中，睾丸从胚胎腹内位置下降到阴囊中。编码类胰岛素 3 肽 (INSL3) 和 GREAT/LGR8 G 蛋白偶联受体的两个基因控制结节的分化，结节是对睾丸下降至关重要的尾部生殖腹股沟韧带。已确定 INSL3 肽在体外激活 GREAT/LGR8 受体。 Insl3 或 Great 的突变会导致小鼠隐睾（睾丸未降）。转基因 Insl3 的过度表达会导致雄性样的生殖器分化、卵巢下降至下腹部位置以及雌性生育力降低。为了解决 Great 缺失是否能补充 Insl3 过表达引起的突变雌性表型的问题，我们制备了 Great 缺陷的 Insl3 转基因小鼠。这些雌性具有野生型表型，表明 Great 是 Insl3 体内唯一的同源受体。我们已经确定，用 INSL3 cDNA 转染的胰腺 HIT 细胞可以产生功能活性肽。对隐睾患者中检测到的五种 INSL3 突变体的分析表明，P49S 取代导致肽功能受损。因此，INSL3 突变可能是隐睾的病因之一。我们还表明，合成的胰岛素样肽（INSL4 和 INSL6）无法激活 LGR7 或 GREAT/LGR8。
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.