The Ron STK receptor tyrosine kinase is essential for peri-implantation development in the mouse

The Ron/STK receptor tyrosine kinase is a member of the c-Met family of rec eptors and is activated by hepatocyte growth factor-like protein (HGFL). Ro n activation results in a variety of cellular responses in vitro, such as a ctivation of macrophages, proliferation, migration, and invasion, suggestin g a broad biologic role in vivo. Nevertheless, HGFL-deficient mice grow to adulthood with few appreciable phenotypic abnormalities. We report here tha t in striking contrast to the loss of its only known ligand, complete loss of Ron leads to early embryonic death. Embryos that are devoid of Ron (Ron( -/-)) are viable through the blastocyst stage of development but fail to su rvive past the peri-implantation period. In situ hybridization analysis dem onstrates that Ron is expressed in the trophectoderm at embryonic day (E) 3 .5 and is maintained in extraembryonic tissue through E7.5, compatible with an essential function at this stage of development. Hemizygous mice (Ron(/-)) grow to adulthood; however, these mice are highly susceptible to endot oxic shock and appear to be compromised in their ability to downregulate ni tric oxide production. These results demonstrate a novel role for Ron in ea rly mouse development and suggest that Ron plays a limiting role in the inf lammatory response.