Genetic targeting of relaxin and Insl3 signaling in mice

Shu Feng, Natalia Bogatcheva, Aparna A. Kamat, Alexander I. Agoulnik

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 Insl3 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 Insl3 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).

Original languageEnglish (US)
Pages (from-to)82-90
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume1041
DOIs
StatePublished - 2005
Externally publishedYes

Fingerprint

Relaxin
Nipples
Insulin
Ligands
Muscle
Rats
Collagen
Tissue
Prostate
Peptides
Parturition
Phenotype
Mutation
Cryptorchidism
Pulmonary Fibrosis
Knockout Mice
Hypertrophy
Transgenic Mice
Smooth Muscle
Testis

Keywords

  • Gene targeting
  • Insl3
  • Lgr7
  • Lgr8/Great
  • Relaxin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Genetic targeting of relaxin and Insl3 signaling in mice. / Feng, Shu; Bogatcheva, Natalia; Kamat, Aparna A.; Agoulnik, Alexander I.

In: Annals of the New York Academy of Sciences, Vol. 1041, 2005, p. 82-90.

Research output: Contribution to journalArticle

Feng, Shu ; Bogatcheva, Natalia ; Kamat, Aparna A. ; Agoulnik, Alexander I. / Genetic targeting of relaxin and Insl3 signaling in mice. In: Annals of the New York Academy of Sciences. 2005 ; Vol. 1041. pp. 82-90.
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AB - 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 Insl3 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 Insl3 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).

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