Ectopic expression of the transforming growth factor beta type II receptordisrupts mesoderm organisation during mouse gastrulation

Transforming growth factor beta (TGF beta) regulates the cell cycle and ext racellular matrix (ECM) deposition of many cells in vitro. We have analysed chimaeric mouse embryos generated from embryonic stem cells with abnormal receptor expression to study the effect of TGF beta on these processes in v ivo and the consequences for normal development. The binding receptor for T GF beta, T beta RII, is first detected in the embryo proper around day 8.5 in the heart. Ectopic expression of T beta RII from the blastocyst stage on ward resulted in an embryonic lethal around 9.5 dpc, Analysis of earlier st ages revealed that the primitive streak of T beta RII chimaeras failed to e longate. Furthermore, although cells passed through the streak and initiall y formed mesoderm, they tended to accumulate within the streak. These defec ts temporally and spatially paralleled the expression of the TGF beta type I receptor, which is first expressed in the node and primitive streak. We p resent evidence that classical TGF beta-induced growth inhibition was proba bly the cause of insufficient mesoderm being available for paraxial and axi al structures. The results demonstrate that (1) TGF beta mRNA and protein d etected previously in early postimplantation embryos is present as a biolog ically active ligand; and (2) assuming that ectopic expression of T beta RI I results in no other changes in ES cells, the absence of T beta RII is the principle reason why the embryo proper is unresponsive to TGF beta ligand until after gastrulation. Dev Dyn 1999:214: 141-151. (C) 1999 Wiley-Liss, I nc.