TGF-β Receptor Type II Deficiency Results in Defects of Yolk Sac Hematopoiesis and Vasculogenesis

Abstract

TGF-beta signaling is mediated through two types of serine/threonin kinase-containing receptors, type I (TGF-betaRI) and type II (TGF-betaRII), which form a heteromeric complex. In this signaling complex, ligand binding TGF-betaRII phosphorylates and thereby activates the TGF-betaRI to signal downstream pathways. To determine the role of TGF-betaRII in embryogenesis, we have generated a TGF-betaRII gene (Tgfbr2) knockout mouse line. The heterozygous Tgfbr2 knockout mice are developmentally normal. The homozygous Tgfbr2 mutation causes defects in the yolk sac hematopoiesis and vasculogenesis, resulting in an embryonic lethality around 10.5 days of gestation. This phenotype is indistinguishable from the previously reported embryonic lethality by the homozygous TGF-beta1 gene (Tgfb1) null mutation. In addition, we have generated chimeric mice using a Tgfbr2 (-/-) embryonic stem cell line. Some chimeric mice showed several types of congenital anomalies, suggesting that TGF-beta II is important for normal development in a variety of organs.

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

“…Importantly, CD31 staining, a marker of endothelial cells (ECs), showed the presence of extensive neovasculature within the T204D tumors and a reduced hypoxia compared to the EGFP tumors, whereas the K232R tumors exhibited a significant reduction in CD31-positive cells (Figure 8). These findings indicate that the effects of TGF-b-ALK5 signaling support recruitment of vascular cells and/or maturation of tumor blood vessels, which is consistent with a critical role of the TGF-b pathway in vasculogenesis found in the studies with targeted disruption of TGF-b1 (Dickson et al, 1995) and TGF-b receptors, type II (Oshima et al, 1996) and type I (Larsson et al, 2001). Suppression of MMP-9 resulted in the collapse of capillary-like vasculature within the T204D tumors and increased tumor cell death, but had little effect on the presence of ECs, suggesting that MMP-9 is likely involved in vessel maturation and to a lesser extent in the recruitment of ECs.…”

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

“…The targeted disruption of TGF-␤1 gene led to early embryonic lethality in about 50% of homozygous as a result of the defects in the yolk sac vasculature and the haematopoietic system (Martin et al, 1995). Similarly, the targeted inactivation of TGF-␤ receptor T␤RII also resulted in defects in yolk sac vasculogenesis and haematopoiesis in homozygous embryos (Oshima et al, 1996). TGF-␤1 strongly induced angiogenesis when administered subcutaneously to newborn or adult mice or rat (Pepper, 1997).…”

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

“…Filters were processed at high stringency as described (Church and Gilbert, 1984). As a hybridization probe the cDNA of the human truncated type II TGF-b receptor or exon 1 of the mouse type II TGF-b receptor were used (Lin et al, 1992;Oshima et al, 1996). Both probes were approximately 700 bp and labeled with similar speci®c activity.…”

“…Furthermore, the tissue speci®c expression cassette targets transgene expression to speci®c tissues. Thereby, embryonic lethality as seen in the type II TGF-b receptor knockout mice is avoided (Oshima et al, 1996). To direct the expression of the transgene to the basal compartment of the epidermis and to hair follicles we used a previously described expression cassette based on the bovine keratin 5 promoter (Blessing et al, 1993;Casatorres et al, 1994;Ramirez et al, 1994).…”