Targeted mutations of transforming growth factor‐β genes reveal important roles in mouse development and adult homeostasis

Abstract

Transforming growth factors‐beta (TGF‐β) are multifunctional molecules with profound biological effects in many developmental processes including regulation of cell proliferation, differentiation, cell adhesion, skeletal development, haematopoiesis, inflammatory responses, and wound healing. To learn about the role of TGF‐β in vivo, phenotypes of targeted mutations of molecules within the TGF‐β signalling pathway, TGF‐β1, ‐β2, ‐β3, TGF‐β receptor (TβR‐II) and the signalling molecules SMAD2, SMAD3 and SMAD4, are discussed in this review. The three individual TGF‐β mutants show distinct and only partially overlapping phenotypes. In mice, targeted disruption of the TGF‐β1 gene results in diffuse and lethal inflammation about 3 weeks after birth, suggesting a prominent role of TGF‐β in the regulation of immune cell proliferation and extravasation into tissues. However, just half of the TGF‐β1 (–/–) conceptuses actually reach partuition due to defective haematopoiesis and endothelial differentiation. Targeted disruption of both TGF‐β2 and TGF‐β3 genes results in perinatal lethality. TGF‐β2 null mice exhibit a broad range of developmental defects, including cardiac, lung, craniofacial, limb, eye, ear and urogenital defects, whereas TGF‐β3 gene ablation results exclusively in defective palatogenesis and delayed pulmonary development. The TβR‐II null phenotype closely resembles that of TGF‐β1 (–/–) conceptuses, which die in utero by E10.5. Loss of SMAD2 or SMAD4 results in related phenotypes: the mutants fail to form an organized egg cylinder, lack mesoderm required for gastrulation and die prior to E8.5. Together, gene ablation within the TGF‐β signalling pathway supports the notion of a prominent role of TGF‐β during development.