Neonatal ovine uterine morphogenesis: mechanisms regulating the development of endometrial glands

Abstract

Uterine glands differentiate and develop after birth in neonatal ewe lambs. Endometrial glands are required for cyclicity and establishment and maintenance of pregnancy in sheep. However, mechanisms regulating endometrial gland morphogenesis are not well characterized in any mammal. Therefore, studies were conducted to determine the role of estradiol- 17β, prolactin and the insulin-like growth factor (IGF) system in endometrial gland morphogenesis or adenogenesis in the uterus of neonatal ewes. The first study determined the ontogeny of estradiol-l7β, prolactin, and their receptors in the uterus from birth to postnatal day (PND) 56. Serum concentrations of estradiol-l7β (E₂-17β) and prolactin (PRL) were high at birth and increased between PNDS 14 and 28 (E₂-17β) and PNDS 1 and 14 (PRL), respectively. Similarly, estrogen receptor-α (ER-α) expression increased in the lumenal epithelium (LE) between PND 0 and PND 1. Between PND 7 and PND 56, ER-α expression was detected in nascent and proliferating glands, with higher expression at the tips of developing glands. Prolactin receptor (PRL--R) expression was also high during uterine glandular morphogenesis, with specific localization between PND 7 and PND 56 in nascent and proliferating endometrial glands. The second study characterized expression of lGF-l, IGF-II, and the IGF-I receptor (lGF-lR) during gland development. Expression of both IGF-I and 1GF-ll mRNAs was localized spatially to endometrial stromal cells surrounding nascent and morphogenetically uterine active glands. IGF-IR mRNA expression was detected in all uterine cell types with higher expression in lumenal and glandular epithelia. Results of this study support the idea that the IGF system and epithelial-mesenchymal interactions regulate endometrial gland development. Collectively, results of these studies implicate roles for E₂-17β, PRL, IGFs and their receptors as regulators of endometrial adenogenesis. Thus, the working hypothesis is that both PRL and IGFs increase in response to E₂-17β and activate the mitogen activated protein kinase (MAPK) signaling cascade and possibly ER-α. Activation of ER-α via ligand-dependent or -independent activation induces cellular proliferation and differentiation of endometrial glands. Therefore, proper development of endometrial glands is necessary for the uterus to achieve its ultimate function, which is to create an environment that supports embryonic and fetal-placental development.