Lysophosphatidic acid regulates murine blastocyst development by transactivation of receptors for heparin-binding EGF-like growth factor

Transient elevation of intracellular calcium (Ca-i(2+)) by various means accelerates murine preimplantation development and trophoblast differentiation. Several G-protein-coupled receptors (GPCRs), including the lysophosphatidic acid (LPA) receptor (LPAR), induce Ca-i(2+) transients and transactivate the EGF receptor (ErbB1) through mobilization of EGF family members, including heparin-binding EGF-like growth factor (HB-EGF). Because HB-EGF accelerates blastocyst differentiation in vitro, we examined whether crosstalk between LPA and HB-EGF regulates peri-implantation development. During mouse blastocyst differentiation, embryos expressed LPAR, mRNA Signaling, LPA rapidly constitutively, LPAR(2) only in late stage blastocysts and no LPAR(3). Consistent with a mechanism based on Ca-i(2+) accelerated the rate of trophoblast outgrowth, an index of blastocyst differentiation, and chelation of Ca-i(2+) with BAPTA-ANI blocked LPA stimulation. Interfering with HB-EGF signaling through ErbB1 or ErbB4 also attenuated LPA stimulation. We established that mouse blastocysts indeed express HB-EGF and that LPA induces the transient accumulation of HB-EGF on the embryo surface, which was blocked by treatment with either BAPTA-AM or the protein trafficking inhibitor, brefeldin A. We conclude that LPA accelerates blastocyst transients and HB-EGF autocrine signaling. Transactivation of ErbB I or ErbB4 by HB-EGF differentiation through its ability to induce Ca-i(2+) represent a convergent signaling pathway accessed in the trophoblast by stimuli that mobilize Ca-i(2+). (C) 2004 Elsevier Inc. All rights reserved.