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 receptors and is activated by hepatocyte growth factor-like protein (HGFL). Ron activation results in a variety of cellular responses in vitro, such as activation of macrophages, proliferation, migration, and invasion, suggesting a broad biologic role in vivo. Nevertheless, HGFL-deficient mice grow to adulthood with few appreciable phenotypic abnormalities. We report here that 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 survive past the peri-implantation period. In situ hybridization analysis demonstrates 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 endotoxic shock and appear to be compromised in their ability to downregulate nitric oxide production. These results demonstrate a novel role for Ron in early mouse development and suggest that Ron plays a limiting role in the inflammatory response.
Muraoka
R S
RS
Graduate Program in Developmental Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Sun
W Y
WY
Colbert
M C
MC
Waltz
S E
SE
Witte
D P
DP
Degen
J L
JL
Friezner Degen
S J
SJ
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D010064:Embryo Implantation; D005314:Embryonic and Fetal Development; D005260:Female; D005313:Fetal Death / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism
D017931:DNA Primers; D011956:Receptors, Cell Surface; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases