The receptor tyrosine kinase Ron is expressed in the mouse ovary and regulates inducible nitric oxide synthase levels and ovulation

Fertil Steril. 2003 Sep;80 Suppl 2:747-54. doi: 10.1016/s0015-0282(03)00774-x.


Objective: To determine the reproductive effects in mice of the deletion of the tyrosine kinase domain of the Ron receptor.

Design: Controlled animal studies.

Setting: Academic research environment.

Animal(s): Immature mice with deletion of the tyrosine kinase domain of the Ron receptor (TK-/-) at 22-30 days of age and adult black Swiss female mice at 5-6 weeks of age.

Intervention(s): Hormonal stimulation of immature female TK-/- animals to induce ovulation.

Main outcome measure(s): Ovulation rates measured by counting the total number of cumulus oocyte complexes in the ampullar region of the murine oviduct after hormonal stimulation. Western blot analysis measured murine ovarian protein levels of endothelial and inducible nitric oxide synthase (iNOS). Immunohistochemical analysis localized iNOS in the developing murine ovarian follicle.

Result: Immature TK-/- mice (22-30 days) ovulate significantly fewer cumulus oocyte complexes. Western blot analyses demonstrated increased levels of iNOS before and after ovulation compared with controls. Conversely, endothelial nitric oxide synthase levels were similar and remained constant during corresponding time periods. Immunohistochemical analyses demonstrated a significant increase in iNOS staining throughout the ovary in TK-/- mice with a significant amount of iNOS in granulosa cells surrounding the oocyte when compared with controls.

Conclusion(s): The increased level of nitric oxide in the TK-/- mice is likely due to an elevated level of iNOS, which may contribute to a decrease in the size of the ovaries and ovulation rates of immature TK-/- animals.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Female
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Nitric Oxide / genetics
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Ovarian Follicle / enzymology*
  • Ovarian Follicle / metabolism
  • Ovulation Induction*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA / chemistry
  • RNA / genetics
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Proto-Oncogene Proteins
  • macrophage stimulating protein
  • Nitric Oxide
  • RNA
  • Hepatocyte Growth Factor
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • RON protein
  • Receptor Protein-Tyrosine Kinases