title: Radiosensitive target in the mouse embryo chimera assay: implications that the target involves autocrine growth factor function.
abstract: Mouse preimplantation embryos express at least two functional cell surface growth factor receptors that are radiosensitive in other cell types, the epidermal growth factor receptor (EGF receptor) and the insulin-like growth factor I receptor (IGF-I receptor). These embryos also express ligands that bind to and activate these receptors, including transforming growth factor alpha (TGF-alpha) and insulin-like growth factor II (IGF-II), which bind to the EGF receptor and IGF-I receptor, respectively. Embryo-expressed IGF-II and TGF-alpha increase embryo cell number--a measure of proliferation rate--and stimulate blastocoele formation--a measure of cell differentiation--allowing the embryo to self-modulate cell proliferation and morphogenesis into a blastocyst (Paria and Dey, Proc. Natl. Acad. Sci. USA 87, 4756-4760, 1990; Dardik and Schultz, Development 113, 919-930, 1991; Rappolee et al., Genes Dev. 6, 939-952, 1992). In this work, we tested the hypothesis that IGF-I receptor and/or EGF receptor function may be impaired to produce the radiation-induced competitive cell proliferation disadvantage that is expressed by irradiated embryos that are aggregated with nonirradiated embryos in chimeras. Cleavage-stage embryos were irradiated with 137Cs gamma rays (0.5 or 1.0 Gy) and paired with nonirradiated same-stage embryos to form groups of chimeras that were cultured in control medium or medium containing IGF-II, insulin, EGF or TGF-alpha. The cell proliferation disadvantage expressed by the irradiated embryos within chimeras was completely eliminated by IGF-II or insulin. In contrast to the rescue action of IGF-II or insulin in chimeras, neither EGF nor TGF-alpha could prevent the cell proliferation disadvantage exhibited by irradiated embryos paired with nonirradiated embryos in chimeras. For irradiated conventionally cultured zona-enclosed embryos, IGF-II and TGF-alpha did not increase mean embryo cell number significantly, although both IGF-II and TGF-alpha did increase blastocoele formation significantly. Collectively, these results support the following conclusions: (1) Ligands for the IGF-I receptor can rescue irradiated embryos from competitive cell proliferation disadvantage in chimeras, while ligands for the EGF receptor cannot; (2) IGF-I receptor function and EGF receptor function are affected differently by ionizing radiation with respect to competitive cell proliferation and are affected similarly by ionizing radiation with respect to blastocoele formation; (3) EGF receptor-dependent stimulation of competitive cell proliferation and cell differentiation are affected differently by ionizing radiation in preimplantation embryos.
authors.affiliation: Institute of Toxicology and Environmental Health, School of Medicine, University of California, Davis 95616-8615, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Peters
authors.forename: E C
authors.initials: EC
authors.lastname: Tsark
authors.forename: L M
authors.initials: LM
authors.lastname: Wiley
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002588:Cesium Radioisotopes; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000528:radiation effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D005720:Gamma Rays; D006133:Growth Substances / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009924:Organ Culture Techniques; D011828:Radiation Chimera; D013480:Superovulation; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D015044:Zona Pellucida / Q000502:physiology
chemical_list: D002588:Cesium Radioisotopes; D006133:Growth Substances; D007328:Insulin; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D007335:Insulin-Like Growth Factor II