Regulation of the differentiation and behaviour of extra-embryonic endodermal cells by basement membranes

Both the extracellular matrix and parathyroid hormone-related peptide (PTHr P) have been implicated in the differentiation and migration of extra-embry onic endodermal cells in the pre-implantation mammalian blastocyst, In orde r to define the individual roles and interactions between these factors in endodermal differentiation, we have used embryoid bodies derived from Lamc1 (-/-) embryonic stem cells that lack basement membranes. The results show t hat in the absence of basement membranes, increased numbers of both viscera l and parietal endodermal cells differentiate, but they fail to form organi sed epithelia, Furthermore, although parietal endodermal cells only migrate away from control embryoid bodies in the presence of PTHrP, they readily m igrate from Lamc1(-/-) embryoid bodies in the absence of PTHrP, and this mi gration is unaffected by PTHrP, Thus, the basement membrane between epiblas t and extra-embryonic endoderm is required for the proper organisation of v isceral and parietal endodermal cells and also restricts their differentiat ion to maintain the population of primitive endodermal stem cells. Moreover , this basement membrane inhibits migration of parietal endodermal cells, t he role of PTHrP being to stimulate delamination of parietal endodermal cel ls from the basement membrane rather than promoting migration per se.