Female Reproductive Tract

WNT Pathways in the Neonatal Ovine Uterus: Potential Specification of Endometrial Gland Morphogenesis by SFRP2

Abstract
Endometrial glands are critical for uterine function and develop between birth (postnatal day 0 or P0) and P56 in the neonatal ewe. Endometrial gland morphogenesis or adenogenesis involves the site-specific budding differentiation of the glandular epithelium (GE) from the luminal epithelium (LE) followed by their coiling/branching development within the stroma of the intercaruncular areas of the endometrium. To determine if WNT signaling regulates endometrial adenogenesis, the WNT signaling system was studied in the neonatal ovine uterus. WNT5A, WNT7A and WNT11 were expressed in the uterine epithelia, whereas WNT2B was in the stroma. The WNT receptors, FZD2 and FZD6, and co-receptor LRP6 were detected in all uterine cells, and FZD6 was particularly abundant in the endometrial epithelia. SFRP2, a WNT antagonist, was not detected in the P0 uterus, but was abundant in the aglandular caruncular areas of the endometrium between P7 and P56. Exposure of ewes to estrogens during critical developmental periods inhibits or retards endometrial adenogenesis. Estrogen-induced disruption of endometrial adenogenesis was associated with reduction or ablation of WNT2B, WNT7A and WNT11 and an increase in WNT2 and SFRP2 mRNA depending on exposure period. Collectively, results implicate the canonical and non-canonical WNT pathways in regulation of postnatal ovine uterine development and endometrial adenogenesis. Expression of SFRP2 in aglandular caruncular areas may inhibit WNT signaling pathway, thereby concentrating WNT signaling and restricting endometrial adenogenesis in the intercaruncular areas of the uterus. Further, estrogen-induced inhibition of adenogenesis may be mediated by a reduction in WNT signaling due to aberrant induction of SFRP2 and loss of several critical WNTs.

Key words: Developmental biology • Estradiol • Kinases • Signal transduction • Uterus

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