Genetic targeting of relaxin and Insl3 signaling in mice

被引:16
作者
Feng, S [1 ]
Bogatcheva, NV [1 ]
Kamat, AA [1 ]
Agoulnik, AI [1 ]
机构
[1] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA
来源
RELAXIN AND RELATED PEPTIDES: FOURTH INTERNATIONAL CONFERENCE | 2005年 / 1041卷
关键词
relaxin; InsI3; Lgr7; Lgr8/Great; gene targeting;
D O I
10.1196/annals.1282.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We studied ligand-receptor interactions between relaxin (RLN), insulin-like 3 peptide (INSL3), and LGR7 and LGR8 receptors. The phenotypic effects of deficiency for Lgr7 and Lgr8 receptors, transgenic overexpression of Rln1 and Insl3, and different combinations of these mutations in mice were analyzed. It was reported that Rln1-deficient mice exhibit abnormal nipple development, prolonged parturition, age-related pulmonary fibrosis, and abnormalities in the testis and prostate. Mutation of Lgr8 or its cognate ligand InsI3 causes cryptorchidism. Mutant females deficient for the Lgr7 receptor have grossly undeveloped nipples and are unable to feed their progeny. Parturition is prolonged in these females, resulting in a significantly higher number of stillborn pups. Histologic analysis of Lgr7 mutant lung tissues demonstrates increased collagen accumulation and perivenular smooth muscle hypertrophy. However, Lgr7-deficient males do not exhibit abnormalities of male reproductive organs as seen in Rln1 knockout mice. Double-mutant males deficient for Lgr7 and Lgr8 have a normal prostate, suggesting that Lgr8 does not account for differences in Rln1(-/-) and Lgr7(-/-) phenotypes. We also produced mice with transgenic overexpression of Rln1 under rat insulin 2 promoter. Rln1 transgenic females exhibited increased nipple size, whereas Rln1 transgenic females deficient in Lgr7 had undeveloped nipples, indicating that Lgr7 is the only receptor for relaxin that mediates this effect. Transgenic overexpression of Rln1 does not affect gonadal descent in females, and transgenic overexpression of InsR does not rescue the mutant phenotype of Lgr7-deficient mice, suggesting the non-overlapping functions of two signaling pathways. In summary, our data indicate that the Insl3/Lgr8 and Rln1/Lgr7 pathways are distinct and separate in vivo. Therefore, we propose to rename Lgr8 as Insl3r (Insl3 receptor) and Lgr7 as Rlnr (relaxin receptor).
引用
收藏
页码:82 / 90
页数:9
相关论文
共 21 条
[1]   Insulin-like 3 signalling in testicular descent [J].
Adham, IM ;
Agoulnik, AI .
INTERNATIONAL JOURNAL OF ANDROLOGY, 2004, 27 (05) :257-265
[2]   The overexpression of the Insl3 in female mice causes descent of the ovaries [J].
Adham, IM ;
Steding, G ;
Thamm, T ;
Büllesbach, EE ;
Schwabe, C ;
Paprotta, I ;
Engel, W .
MOLECULAR ENDOCRINOLOGY, 2002, 16 (02) :244-252
[3]   GREAT/LGR8 is the only receptor for insulin-like 3 peptide [J].
Bogatcheva, NV ;
Truong, A ;
Feng, S ;
Engel, W ;
Adham, IM ;
Agoulnik, AI .
MOLECULAR ENDOCRINOLOGY, 2003, 17 (12) :2639-2646
[4]   Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist [J].
Dschietzig, T ;
Bartsch, C ;
Stangl, V ;
Baumann, G ;
Stangl, K .
FASEB JOURNAL, 2004, 18 (11) :1536-+
[5]   Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype [J].
Du, XJ ;
Samuel, CS ;
Gao, XM ;
Zhao, L ;
Parry, LJ ;
Tregear, GW .
CARDIOVASCULAR RESEARCH, 2003, 57 (02) :395-404
[6]  
FENG S, 2004, UNPUB ENDOCRINE EFFE
[7]   Mutations of the GREAT gene cause cryptorchidism [J].
Gorlov, IP ;
Kamat, A ;
Bogatcheva, NV ;
Jones, E ;
Lamb, DJ ;
Truong, A ;
Bishop, CE ;
McElreavey, K ;
Agoulnik, AI .
HUMAN MOLECULAR GENETICS, 2002, 11 (19) :2309-2318
[9]   Activation of orphan receptors by the hormone relaxin [J].
Hsu, SY ;
Nakabayashi, K ;
Nishi, S ;
Kumagai, J ;
Kudo, M ;
Sherwood, OD ;
Hsueh, AJW .
SCIENCE, 2002, 295 (5555) :671-674
[10]   The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): Identification of LGR6 and LGR7 and the signaling mechanism for LGR7 [J].
Hsu, SY ;
Kudo, M ;
Chen, T ;
Nakabayashi, K ;
Bhalla, A ;
van der Spek, PJ ;
van Duin, M ;
Hsueh, AJW .
MOLECULAR ENDOCRINOLOGY, 2000, 14 (08) :1257-1271