Embryo implantation into the uterine wall is a highly regulated and vital event of early mammalian development. Following hatching from the zona pellucida, the trophectodermal cells surrounding the embryo develop to an attachment competent state. Attachment competent embryos are capable of attaching to and invading a wide variety of cell and tissue types. The uterus appears to be unique in the sense that it is the only known tissue capable of regulating the invasive potential of the trophoblast. Under most conditions, the uterus is """"""""non-receptive"""""""" and will not allow embryos to attach. Conversion to a receptive uterine state is transient and normally coordinated with the development of the embryo by the actions of estrogen and progesterone. The task of regulating uterine receptivity is relegated to the cells lining the uterine lumen, the uterine epithelial cells (UEC). In this regard, a number of morphological studies indicate that the composition of cell surface polysaccharides alters dramatically on both trophectodermal and UEC cell surfaces at the time of embryo attachment. These changes may include loss of inhibitors of embryo attachment as well as induction of embryo """"""""receptors"""""""". Finally, in many species, the uterus differentiates locally (decidual cell reaction) in response to the attaching embryo. Therefore, implantation models must consider how embryo attachment signals are transduced through UEC to underlying stroma. Studies from the PI's lab have demonstrated that mucin glycoproteins of the apical cell surface of uterine epithelial cells (UEC) provide a protective barrier to invasion by embryos or highly invasive tumor cells. Furthermore, mucin glycoprotein expression is down-regulated prior to the time of embryo attachment in utero. Other studies from the PI's lab strongly implicate binding of embryonic heparan sulfate (HS) proteoglycans to HS-binding sites of UEC as key aspects of embryo attachment to UEC. Finally, other experiments indicate that tenascin (TN), an extracellular matrix glycoprotein which appears to disrupt cell adhesion events and may bind growth factors elaborated by UEC, is rapidly induced in the uterine stroma immediately subjacent to the site of embryo attachment in utero. A model if proposed which separates the periimplantation stage into three phases: 1) non-receptive characterized by high level mucin expression which prevents embryo attachment; 2) receptive characterized by low mucin expression and increased exposure of HS binding sites at the apical surface of UEC to support embryo attachment and; 3) preinvasive in which TN is expressed in stroma underlying the implantation site and facilitates embryo penetration. We will use specific probes and established detection methods to study the expression of these markers of uterine receptivity in vivo and in vitro. A newly developed in vitro UEC-uterine stromal cell recombinant system will be employed to identify potential regulators of the expression of each marker. We will attempt to restore control of UEC receptivity in vitro and further test the function of mucin glycoproteins, HS binding sites and TN.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (SRC (02))
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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Julian, Joanne; Dharmaraj, Neeraja; Carson, Daniel D (2009) MUC1 is a substrate for gamma-secretase. J Cell Biochem 108:802-15
Wang, Peng; Julian, Joanne A; Carson, Daniel D (2008) The MUC1 HMFG1 glycoform is a precursor to the 214D4 glycoform in the human uterine epithelial cell line, HES. Biol Reprod 78:290-8
Brayman, Melissa Jo; Dharmaraj, Neeraja; Lagow, Errin et al. (2007) MUC1 expression is repressed by protein inhibitor of activated signal transducer and activator of transcription-y. Mol Endocrinol 21:2725-37
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Tang, Meiyi; Mikhailik, Anatoly; Pauli, Ilse et al. (2005) Decidual differentiation of stromal cells promotes Proprotein Convertase 5/6 expression and lefty processing. Endocrinology 146:5313-20
Al-Shami, Rania; Sorensen, Esben S; Ek-Rylander, Barbro et al. (2005) Phosphorylated osteopontin promotes migration of human choriocarcinoma cells via a p70 S6 kinase-dependent pathway. J Cell Biochem 94:1218-33
Tang, Meiyi; Xu, Yun; Julian, Joanne et al. (2005) Lefty is expressed in mouse endometrium in estrous cycle and peri-implantation period. Hum Reprod 20:872-80
Brayman, Melissa; Thathiah, Amantha; Carson, Daniel D (2004) MUC1: a multifunctional cell surface component of reproductive tissue epithelia. Reprod Biol Endocrinol 2:4

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