Tgfß2 ^–/– Tgfß3 ^–/– double knockout mice display severe midline fusion defects and early embryonic lethality

Abstract.

Given all known biological activities, it is anticipated that transforming growth factors beta (TGF-ßs) play important roles in many different developmental processes. As all three TGF-ß isoforms display overlapping expression patterns, deletion of one TGF-ß isoform might be compensated for by another. In the present study, targeted disruption of both Tgfß2 and Tgfß3 genes was undertaken to circumvent this problem and determine the essential roles of TGF-ß2 and TGF-ß3 in vivo. Tgfß2 ^–/– Tgfß3 ^–/– double knockout mice and their three-allelic Tgfß2 ^–/– Tgfß3 ^+/– littermates display a lack of distal parts of the rib, a lack of sternal primordia, and failure in ventral body wall closure, leading to an extrathoracic position of the heart and extrusion of the liver. In addition, abnormalities in connective tissue composition and an early embryonic lethality [around embryonic day (E) 15.5] are seen. In contrast, Tgfß2 ^+/– Tgfß3 ^–/– littermates show normal rib and sternum development, normal anterior body wall fusion, and are still alive on E18.5. TGF-ß2 is already known to play a role in skeletal and craniofacial development. The results presented here show that beyond this: (a) TGF-ßs obviously play a fundamental role in midline fusion and (b) the Tgfß2 gene seems to play a more important role in mediating developmental processes than the Tgfß3 gene, since Tgfß2 ^+/– Tgfß3 ^–/– mutants – in contrast to their Tgfß2 ^–/– Tgfß3 ^{+ /–} littermates – do not display severe malformations.