E–cadherin (CDH1) is a cell–cell adhesion molecule expressed in the epithelium to coordinate key morphogenetic processes, establish cell polarity, and regulate epithelial differentiation and proliferation. CDH1 forms adherens junctions that mediate intercellular adhesion through dynamic interactions with β–catenin (CTNNB1). To determine the role of CDH1 in the mouse uterus, Cdh1 was conditionally ablated by crossing Pgr–Cre and Cdh1–flox mice. Animals with the resulting genotype of Pgrcre/+Cdh1f/f had Cdh1 conditionally ablated in the Pgr expressing tissue, which includes the uterus (referred to as Cdh1d/d). We characterized the phenotype and found that loss of Cdh1 in the neonatal uterus results in a disorganized cellular structure of the epithelium and ablation of endometrial glands. Cdh1d/d mice lost adherens junction (CTNNB1 and CTNNA1) and tight junction (claudin, occludin and ZO–1) in the neonatal uterus leading to loss of epithelial cell–cell interaction. Ablation of Cdh1 induced abnormal epithelial proliferation and massive apoptosis, and disrupted Wnt and Hox gene expression in the neonatal uterus. Although the uteri of Cdh1d/d mice did not show any defect of myometrium, ablation of Cdh1 inhibited stromal (CD10) markers. In addition, a conditional knockout of Ctnnb1 in the uterus and a double conditional knockout of Cdh1&Ctnnb1 in the uterus were created to determine if the uterine defects were caused by an alteration in CDH1, CTNNB1, or a combination of both. Ctnnb1 and Cdh1&Ctnnb1 were conditionally ablated in the uterus by crossing Pgr–Cre and Ctnnb1–flox mice or Cdh1&Ctnnb1–flox mice. The Ctnnb1d/d mice maintained adhesive epithelial characteristics and did not lose adherens junction or tight junction proteins; however ablation of Ctnnb1 induced epithelial hyperplasia and disrupted Wnt and Hox gene expression in the neonatal uterus. The Cdh1d/dCtnnb1d/d mice carried a similar phenotype to the Cdh1d/d mice. Adult Cdh1d/d mice were infertile due to defects during implantation and decidualization. Collectively, these findings suggest that CDH1 has an important role in structural and functional development of the uterus as well as adult uterine function. CDH1 has a capacity to control cell fate by altering directional cell proliferation and apoptosis.

Raising replacement heifers consumes a large portion of dairy and beef producers' income. An ultimate goal of producers is to decrease inputs and maximize outputs to produce fertile replacement heifers. Manipulating early postnatal growth and development through diet enables this practice to be successful. Puberty is greatly influenced by body weight (BW). Once heifers reach puberty, they become fertile and can achieve their reproductive potential. Growth can easily be influenced during the preweaning phase of development. Offering calves a higher plane of nutrition through milk diets prior to weaning hastens development and can lead to an earlier age at the onset of puberty. The objective of the first study was to understand how plane of nutrition influences BW, bone mineralization, and organ growth during the preweaning phase of development in Holstein calves. Calves offered a higher plane of nutrition experienced greater BW gains, increased bone mineralization, and accelerated organ growth. The second study evaluated plane of nutrition on reproductive development, specifically adenogenesis in Holstein heifer calves. Adenogenesis, or the development of uterine glands, is initiated in the early postnatal period. It involves rapid endometrial epithelial cell proliferation, germinal bud formation, invasion into the stroma, and extensive branching and coiling. Little is known about how nutrition impacts adenogenesis in ungulates, however, this study provided validation that it does drive gland formation. Additionally, this study assessed the influence of exogenous estradiol on reproductive development and adenogenesis when given after the completion of adenogenesis. We can confirm that exogenous estradiol given after the completion of adenogenesis does not alter the outcomes of gland formation. The beneficial effects of feeding a higher plane of nutrition to calves prior to weaning on bone mineral density, organ growth, and adenogenesis may provide new possibilities for understanding the impacts of early nutrition on calf immune responses and productive lifespan of the cow. Collectively, these studies emphasize the importance of nutrition during preweaning growth and development of Holstein calves. / Master of Science