Uterine glands: development, function and experimental model systems

Abstract

Development of uterine glands (adenogenesis) in mammals typically begins during the early post-natal period and involves budding of nascent glands from the luminal epithelium and extensive cell proliferation in these structures as they grow into the surrounding stroma, elongate and mature. Uterine glands are essential for pregnancy, as demonstrated by the infertility that results from inhibiting the development of these glands through gene mutation or epigenetic strategies. Several genes, including forkhead box A2, beta-catenin and members of the Wnt and Hox gene families, are implicated in uterine gland development. Progestins inhibit uterine epithelial proliferation, and this has been employed as a strategy to develop a model in which progestin treatment of ewes for 8 weeks from birth produces infertile adults lacking uterine glands. More recently, mouse models have been developed in which neonatal progestin treatment was used to permanently inhibit adenogenesis and adult fertility. These studies revealed a narrow and well-defined window in which progestin treatments induced permanent infertility by impairing neonatal gland development and establishing endometrial changes that result in implantation defects. These model systems are being utilized to better understand the molecular mechanisms underlying uterine adenogenesis and endometrial function. The ability of neonatal progestin treatment in sheep and mice to produce infertility suggests that an approach of this kind may provide a contraceptive strategy with application in other species. Recent studies have defined the temporal patterns of adenogenesis in uteri of neonatal and juvenile dogs and work is underway to determine whether neonatal progestin or other steroid hormone treatments might be a viable contraceptive approach in this species.

Keywords: adenogenesis; contraception; endometrium; murine; ungulate.

Figure 1

Uterine morphology, radial patterning and post-natal development in rodents, sheep and pigs. (A) Diagrams of ideal frontal sections of uterine types. The drawings cut the oviducts off near the uterotubal junctions, and the vaginas just caudal to the cervices. Rodents (rats and mice) have a long duplex type of uterus with dual cervices. Pigs have a long bicornuate uterus with a short uterine body and a single cervix. Sheep have a medium-length bicornuate type of uterus and a short uterine body and a single cervix. (B) Diagrams of ideal radial patterns of the uterine wall. Curved lines in the endometrium denote the tubular, coiled and branched glands that extend from the uterine lumen to the inner myometrium. The rodent uterus contains only a few endometrial glands. The sheep uterus contains large numbers of glands in the intercaruncular areas of the endometrium, whereas the caruncles are glandless. The pig uterus contains large numbers of glands throughout the endometrium. (C) Histoarchitectural development of the uterine wall in the neonatal mouse, sheep and pig. The post-natal (P) age in days is shown in the bottom left of the images. Car, caruncle; LE, luminal epithelium; GE, glandular epithelium; S, stroma; M, myometrium. Reprinted from Spencer et al. (2012) with permission.

Figure 2

Hypothesized role of Wnt and Hox genes in radial patterning and gland formation in the post-natal uterus. Wnt7a and canonical WNT signaling via beta-catenin is required for correct epithelial organization, the radial growth and patterning of the adjacent mesenchymal cells, and the organization of the smooth muscle layers. Wnt7a is required for maintenance (dotted arrows) of Wnt5a, Wnt4, Hoxa10 and Hoxa11 gene expression. Wnt5a signals cooperate with an unknown factor to allow Wnt7a repression that may be requisite for gland formation. Foxa2 governs GE differentiation from the LE and development. Adapted from Mericskay et al. (2004).

Figure 3

Estrogen-sensitive, ESR1-dependent uterine gland genesis in the neonatal pig. A spectrally unmixed composite multispectral image depicting neonatal porcine endometrium from P5. Nascent glandular epithelium (GE) differentiates from luminal epithelium (LE) shortly after birth and begins to penetrate endometrial stroma (S). Differentiation of GE from LE is marked by intense, GE-specific signal for ESR1 (green). Epithelium (LE and GE) is differentiated from stroma by signal specific labeling for cytokeratin-8 (yellow). Cell nuclei were stained using DAPI (blue). Cells positive for the cell proliferation marker MKI67 are indicated by a pink signal. Scale bar = 50 μm.

Figure 4

Cell proliferation and adenogenesis in the neonatal canine uterus visualized by immunostaining for MKI67, a marker of cell proliferation (A) Cell proliferation was robust in both luminal epithelium (LE) and stroma (S) of the 1-week-old canine uterus. Adenogenesis was just beginning at this time, as evidenced by budding of epithelium into the underlying stroma. (B) In the 4-week-old canine uterus, proliferation of glandular (GE) and LE epithelium was reduced compared with the epithelial proliferation seen in the 1-week-old animal. Stromal proliferation was similarly reduced. At this age, glands are clearly seen, and they have extended some distance through the stroma. Scale bar = 50 μm for both photos.