In sheep, uterine development begins during fetal life but is only completed postnatally with proliferation and branching morphogenetic differentiation of the endometrial glandular epithelium (G) from the luminal epithelium (L) between birth or Postnatal Day (PND) 0 and PND 56. In other epithelial-mesenchymal organs, fibroblast growth factor (FGF)-7 and FGF-10, hepatocyte growth factor (HGF), and insulin-like growth factor (IGF)-I and IGF-II play essential roles in ductal branching morphogenesis. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization analyses were used to study temporal and spatial alterations in expression of mRNAs for growth factors (FGF-7, FGF-10, HGF, IGF-I, IGF-II) and their respective receptors (FGF receptor or FGFR2IIIb, c-met, and IGF-IR) in the developing neonatal ovine uterus. The RT-PCR analyses indicated that expression of FGF-10, HGF, IGF-I, and IGF-II mRNAs increased in the neonatal uterus between PND 1 and 56. In situ hybridization analyses indicated that FGFR2IIIb and c-met mRNAs were expressed solely in uterine L and developing G, whereas IGF-IR was expressed in all uterine cell types, with highest levels in L and developing G. Both IGF-I and IGF-II mRNAs were expressed in the endometrial stroma and myometrium, with IGF-I predominantly in the intercaruncular endometrial stroma. The highest levels of IGF-I and IGF-II mRNA expression were detected in the intercaruncular endometrial stroma surrounding the nascent and proliferating glands. Immunohistochemistry revealed that phosphorylated extracellular regulated kinases-1 and -2 were most abundantly expressed in the nascent and proliferating glands of the developing neonatal uterine wall. These results implicate FGF-7, FGF-10, HGF, IGF-I, IGF-II, and their epithelial receptors in epithelial-mesenchymal interactions regulating endometrial gland morphogenesis in the neonatal sheep uterus.
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