Lysophosphatidic acid regulates murine blastocyst development by transactivation of receptors for heparin-binding EGF-like growth factor.
Transient elevation of intracellular calcium (Ca2+(i)) by various means accelerates murine preimplantation development and trophoblast differentiation. Several G-protein-coupled receptors (GPCRs), including the lysophosphatidic acid (LPA) receptor (LPAR), induce Ca2+(i) 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 LPAR1 mRNA constitutively, LPAR2 only in late stage blastocysts and no LPAR3. Consistent with a mechanism based on Ca2+(i) signaling, LPA rapidly accelerated the rate of trophoblast outgrowth, an index of blastocyst differentiation, and chelation of Ca2+(i) with BAPTA-AM 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 differentiation through its ability to induce Ca2+(i) transients and HB-EGF autocrine signaling. Transactivation of ErbB1 or ErbB4 by HB-EGF could represent a convergent signaling pathway accessed in the trophoblast by stimuli that mobilize Ca2+(i).
Liu
Zitao
Z
C.S. Mott Center for Human Growth and Development, Departments of Obstetrics and Gynecology, and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Armant
D Randall
DR
D000818:Animals; D019898:Autocrine Communication; D001755:Blastocyst / Q000166:cytology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D010064:Embryo Implantation; D004622:Embryo, Mammalian; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids / Q000502:physiology*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000166:cytology
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C032881:lysophosphatidic acid; D002118:Calcium