Ectopic expression of the transforming growth factor beta type II receptor disrupts mesoderm organisation during mouse gastrulation.
Transforming growth factor beta (TGFbeta) regulates the cell cycle and extracellular 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 TGFbeta on these processes in vivo and the consequences for normal development. The binding receptor for TGFbeta, TbetaRII, is first detected in the embryo proper around day 8.5 in the heart. Ectopic expression of TbetaRII from the blastocyst stage onward resulted in an embryonic lethal around 9.5 dpc. Analysis of earlier stages revealed that the primitive streak of TbetaRII chimaeras failed to elongate. Furthermore, although cells passed through the streak and initially formed mesoderm, they tended to accumulate within the streak. These defects temporally and spatially paralleled the expression of the TGFbeta type I receptor, which is first expressed in the node and primitive streak. We present evidence that classical TGFbeta-induced growth inhibition was probably the cause of insufficient mesoderm being available for paraxial and axial structures. The results demonstrate that (1) TGFbeta mRNA and protein detected previously in early postimplantation embryos is present as a biologically active ligand; and (2) assuming that ectopic expression of TbetaRII results in no other changes in ES cells, the absence of TbetaRII is the principle reason why the embryo proper is unresponsive to TGFbeta ligand until after gastrulation.
Hubrecht Laboratory, Netherlands Institute of Developmental Biology, Utrecht.
A
A
Zwijsen
M J
MJ
Goumans
K A
KA
Lawson
M A
MA
Van Rooijen
C L
CL
Mummery
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002678:Chimera / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D005326:Fetal Proteins; D005353:Fibronectins / Q000032:analysis; D005455:Fluorescent Antibody Technique; D005775:Gastrula / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D051901:Smad4 Protein; D020825:T-Box Domain Proteins; D014018:Tissue Distribution; D015534:Trans-Activators / Q000032:analysis; D014157:Transcription Factors / Q000032:analysis; D001616:beta-Galactosidase / Q000032:analysis; D000098908:Brachyury Protein
D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D005353:Fibronectins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051901:Smad4 Protein; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D001616:beta-Galactosidase; D000098908:Brachyury Protein; C497783:Smad2 protein, mouse; C490810:Smad4 protein, mouse