TGF beta 1 and TGF beta 3 are partially redundant effectors in brain vascular morphogenesis

摘要

Gene deletion experiments have shown that the three TGF beta isoforms regulate distinct developmental processes. Recent work by our group and others showed that the integrins alpha v beta 6 and alpha v beta 8 activate latent forms of TGF beta 1 and TGF beta 3. This raises the possibility that TGF beta 1 and TGF beta 3 act redundantly in developmental processes where both isoforms are expressed and activation is by integrins. To investigate this issue, we generated mice with defective integrin-mediated TGF beta 1 activation (Tgfb1(RGE/RGE)) that were also homozygous for a null mutation in the TGF beta 3 gene. Tgfb1(RGE/RGE); Tgfb3(-/-) mice have severely perturbed development of the brain vasculature that is highly similar to that in mice lacking alpha v beta 8. Some Tgfb1(RGE/RGE); Tgfb3(+/-) and Tgfb1(RGE/RGE); Tgfb3(+/+) mice have milder, background-dependent versions of the phenotype. In addition, we found that Tgfb3 gene status influences embryonic lethality due to TGF beta 1 deficiency after limited backcrossing to the BALB/c background. Conversely, Tgfb1 gene status modifies the extent of palate fusion in Tgfb3(-/-) mice after limited backcrossing to the ICR background. Our results are consistent with a functional connection between TGF beta 1 and TGF beta 3 during development based on a shared mechanism of activation.