Parathyroid hormone-related peptide (PTHrP) induces parietal endoderm formation exclusively via the Type I PTH/PTHrP receptor

A number of studies suggest a role for PTHrP and the classical PTH/PTHrP re ceptor (type I) in one of the first differentiation processes in mouse embr yogenesis, i.e. the formation of parietal endoderm (PE). We previously repo rted that although in type I receptor (-/-) embryos PE formation seemed nor mal, the embryos were smaller from at least day 9.5 p.c. and 60% had died b efore day 12.5 p.c. Here we show that the observed growth defect commences even earlier, at day 8.5 p.c. Using two novel antibodies, we show that the expression of the type I receptor protein at this stage is confined to extr aembryonic endoderm only. In addition, we show that large amounts of PTHrP protein are present in the adjacent trophoblast giant cells, suggesting a p aracrine interaction of PTHrP and the type I PTH/PTHrP receptor in PE forma tion. The involvement in PE differentiation of other recently described rec eptors for PTHrP would explain a possible redundancy for the type I recepto r in PE formation. However, deletion of the type I PTH/PTHrP receptor in ES cells by homologous recombination completely prevents PTHrP-induced PE dif ferentiation. Based upon these observations, we propose that PTHrP and the type I PTH/PTHrP receptor, although not required for the initial formation of PE, are required for its proper differentiation and/or functioning. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.