Twisted gastrulation mutation suppresses skeletal defect phenotypes in Crossveinless 2 mutant mice

Bone morphogenetic protein (BMP) signaling controls various aspects of organogenesis, including skeletal development. We previously demonstrated that the pro-BMP function of Crossveinless 2 (Cv2) is required for axial and non-axial skeletal development in mice. Here, we showed that skeletal defects in the Cv2-null mutant were reversed by the additional deletion of Twisted gastrulation (Tsg). Whereas the Cv2(-/-) mutant lacks a substantial portion of the lumbar vertebral arches, Cv2(-/-);Tsg(-/-) mice have almost normal arches. Suppression of Cv2(-/-) phenotypes is also seen in the non-axial skeleton, including the ribs, humerus, skull, and laryngeal and tracheal cartilages. In contrast, the Tsg(-/-) phenotype in the head is not significantly affected by the Cv2 mutation. These findings demonstrate that Tsg mutation is epistatic to Cv2 mutation in the major skeletal phenotypes, suggesting that the pro-BMP activity of Cv2 is, at least in part, dependent on Tsg. We also present genetic evidence for the context-dependent functional relationship between Tsg and Cv2 during mouse development.