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. 2001 Dec;21(24):8329-35.
doi: 10.1128/MCB.21.24.8329-8335.2001.

Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases

M Nomi  1 , I Oishi, S Kani, H Suzuki, T Matsuda, A Yoda, M Kitamura, K Itoh, S Takeuchi, K Takeda, S Akira, M Ikeya, S Takada, Y Minami
Affiliations

Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases

M Nomi et al. Mol Cell Biol. 2001 Dec.

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 that mRor1-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 with mRor2 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.

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Figures

FIG. 1
FIG. 1
Targeted disruption of the mRor1 gene. (A) Targeting strategy. The wild-type mRor1 locus, targeting vector, and predicted mutant locus are shown. The exon (including the Ig-like domain), PGK-tk, and PGK-neo are depicted as open boxes. B, BamHI; E, EcoRI; H, HincII; HSV-tk, herpes simplex virus thymidine kinase. (B) Southern blot analysis of fetal DNA. Genomic DNA isolated from yolk sacs of embryos was digested with EcoRV and HincII and hybridized with the EcoRI-HincII probe shown in panel A. Sizes of bands are in kilobases. (C) Gross appearance of wild-type (WT) and mutant newborns. While the mRor1−/− newborn looks essentially identical to the WT newborn, the mRor2−/− newborn is small and cyanotic and has short limbs and tail. Enhancement of mRor2−/− phenotypes is observed in mRor1−/−; mRor2−/− newborns.
FIG. 2
FIG. 2
Histological analysis of the lung. Respiratory malfunction was identified in mRor1−/− and mRor2−/− newborns. Postmortem histological analysis of the lung demonstrates that the alveolar air sacs in the mutant newborns are not fully expanded as they are in the wild-type (WT) control littermate. In addition, pulmonary bleeding was observed in the mutant mice.
FIG. 3
FIG. 3
Examination of craniofacial bones and appendicular skeletons. The craniofacial bones and appendicular skeletons from wild-type (WT), mRor1−/−, and mRor2−/− newborns and double mutant embryos (E19.5) were double stained with Alizarin red and Alcian blue as described in Materials and Methods. Lateral views of the skeleton of the head (A to D) and extremities (forelimb [E to H] and hind limb [I to L]) from wild-type and mutant newborns and a double mutant embryo are shown. Asterisks and arrowheads, dysplasia of the distal and proximal parts of limb bones in mRor2−/− and double mutant mice, respectively. In some cases, apparently delayed ossification of the cranial suture was also observed (data not shown).
FIG. 4
FIG. 4
Examination of ribs, sternal bone, vertebrae, and pelvic bones. The skeletons in wild-type (WT)and mutant newborns and double mutant embryos were double stained with Alizarin red and Alcian blue. Lateral (A to D), ventral (E to H), and dorsal (I to L) views are shown. Arrow and arrowhead, sternal defect (D) and dysplasia of the symphysis of the pubic bone (H) in mRor1/mRor2 mice, respectively. The sternal defect and dysplasia of the symphysis of the pubic bone were observed in 100% (four of four) and 25% (one of four) of the double mutant mice.
FIG. 5
FIG. 5
Histological analysis of hematoxylin-and-eosin-stained longitudinal sections through hearts from wild-type (WT), mRor1−/−, and mRor2−/− newborns and a double mutant embryo (E19.5). The hearts of mRor1−/− newborns exhibit no apparent abnormalities. Asterisks indicate cardiac VSD in the mRor2−/− newborn and the mRor1−/−; mRor2−/− embryo (D) and the complete transposition of the great arteries in the mRor1−/−; mRor2−/− embryo (E). The complete transposition of the great arteries with a situs solitus was observed and was characterized by a discordant arterial connection, while the atrioventricular connection was concordant (E) (3, 6). Serial sections revealed that the pulmonary artery (PA) arising from the left ventricle (LV) ran into the lung directly and that the aorta (Ao) ran out from the right ventricle (RV) in the double mutant embryo (data not shown). The spleen was found on the left side of the abdominal cavity of the double mutant embryo, and neither situs inversus nor asplenia was observed (data not shown). Bar, 300 μm.
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