Loss of mRor1 Enhances the Heart and Skeletal Abnormalities in mRor2-Deficient Mice: Redundant and Pleiotropic Functions of mRor1 and mRor2 Receptor Tyrosine Kinases

Abstract

The mammalian Ror family of receptor tyrosine kinases consists of two structurally related proteins, Ror1 and Ror2. We have shown that mRor2-deficient mice exhibit widespread skeletal abnormalities, ventricular septal defects in the heart, and respiratory dysfunction, leading to neonatal lethality (S. Takeuchi, K. Takeda, I. Oishi, M. Nomi, M. Ikeya, K. Itoh, S. Tamura, T. Ueda, T. Hatta, H. Otani, T. Terashima, S. Takada, H. Yamamura, S. Akira, and Y. Minami, Genes Cells 5:71–78, 2000). Here we show thatmRor1-deficient mice have no apparent skeletal or cardiac abnormalities, yet they also die soon after birth due to respiratory dysfunction. Interestingly, mRor1/mRor2 double mutant mice show markedly enhanced skeletal abnormalities compared withmRor2 mutant mice. Furthermore, double mutant mice also exhibit defects not observed in mRor2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone, and complete transposition of the great arteries. These results indicate that mRor1 and mRor2 interact genetically in skeletal and cardiac development.

ACKNOWLEDGMENTS

We thank M. Lamphier for a critical reading of the manuscript.

This work was supported by a Research Grant for Cardiovascular Diseases and a Research Grant for Comprehensive Research on Aging and Health from the Ministry of Health and Welfare of Japan (Y.M.) and by the Uehara Memorial Foundation (Y.M.), the Kowa Life Science Foundation (Y.M.), the Yamanouchi Foundation for Research on Metabolic Disorders (Y.M.), the Hyogo Science and Technology Association (I.O.), Nippon Boehringer Ingelheim Co., Ltd., Kawanishi Pharma Research Institute (Y.M.), and Daiichi Pharmaceutical Co., Ltd. (Y.M.).