TGFβ1 and TGFβ3 are partially redundant effectors in brain vascular morphogenesis

Abstract

Gene deletion experiments have shown that the three TGFbeta isoforms regulate distinct developmental processes. Recent work by our group and others showed that the integrins alphavbeta6 and alphavbeta8 activate latent forms of TGFbeta1 and TGFbeta3. This raises the possibility that TGFbeta1 and TGFbeta3 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 TGFbeta1 activation (Tgfb1(RGE/RGE)) that were also homozygous for a null mutation in the TGFbeta3 gene. Tgfb1(RGE/RGE); Tgfb3(-/-) mice have severely perturbed development of the brain vasculature that is highly similar to that in mice lacking alphavbeta8. 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 TGFbeta1 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 TGFbeta1 and TGFbeta3 during development based on a shared mechanism of activation.

Molecular Basis of the Ligand Binding Specificity of αvβ8 Integrin

“…Mice deficient in the expression of the integrin ␤8 subunit exhibit variable embryonic lethality because of vasculogenesis failure and severe brain hemorrhage (12), as is the case with mice deficient for integrin ␣v subunit expression (11). Notably, when mice with a TGF-␤1 gene knock-in mutation that causes an RGE substitution of the RGD motif are crossed with TGF-␤3-deficient mice they die as a result of severe brain hemorrhage (51), recapitulating the phenotype of integrin ␤8-deficent mice. Given the similarities in phenotypes between ␣v␤8 integrin-deficient mice and TGF-␤1(RGE)/TGF-␤3 double mutant mice, ␣v␤8 integrin has been proposed to act as an "angiogenic switch" in the brain through TGF-␤ activation (52,53).…”

Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

“…35 Moreover, when the TGF-␤1 (RGE) mice were crossed to a TGF-␤3 null background, they almost completely recapitulated the early yolk sac vascular defects and the perinatal hemorrhagic brain vascular phenotype of the ␣v-or ␤8 subunit-deficient mice. 13 These experiments suggest that the ␣v␤8 integrin is a crucial regulator of the vasculogenic TGF-␤1 and 3 function during development via interaction with the LAP RGD integrin-binding domain.…”

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

“…Specifically, Itgb8 -/ -mice treated perinatally with an antibody that blocks avb6 develop the immunological features of Tgfb1 -/ -mice (severe multiorgan inflammation and absence of Langerhans cells), and Itgb6 -/ -;Itgb8 -/ -mice have a high incidence of cleft palate, the main finding in TGF-b3-null mice (Aluwihare et al 2009). Conversely, Tgfb1 RGE/RGE ;Tgfb3 -/ -mice are all born with brain hemorrhage, the only phenotype in mice lacking avb8 that is not seen in mice lacking just TGF-b1 or TGF-b3 (Mu et al 2008). Thus, avb6 and Lyons et al (1990) and Flaumenhaft et al (1992); osteoclast data from Oursler (1994); MMP-13 data from Uchinami et al (2006) and Nannuru et al (2010); TSP1 data from Crawford et al (1998); Itgav 2/2 data from Bader et al (1998); avb6 data from Munger et al (1999); avb8, MT1-MMP data from Mu et al (2002); avb3, avb5 data from Wipff et al (2007); ROS data from Jobling et al (2006); shear force data from Ahamed et al (2008).…”