Instrumental to fetal-maternal exchange during parturition is a correctly formed and functioning chorio-allantoic placenta. Though it has received scant attention, the allantois-derived umbilical component of the placenta forms a perfectly aligned vascular bridge between the fetus and its mother. Despite the importance of this bridge, how it is established is not known. Recently, our studies of Brachyury (T) revealed that the allantois contains spatial coordinates that direct formation of a correctly patterned umbilical plexus and align it with respect to the embryonic antero-posterior axis. This finding gave us the first insight into the developmental relationship between the embryo and its umbilical cord. Specifically, T protein identified a novel allantoic region, which we have named the Allantoic Core Domain (ACD). In the absence of the T-defined ACD, the allantois neither elongated nor properly vascularized. Preliminary data unexpectedly revealed that the ACD generates and patterns a primary umbilical vasculature, then properly aligns it with the embryo. An integrative approach of classical methods of embryology, molecular biology and genetics will be used to address five specific aims: (1) To discover the source of the ACD's impressive generative potential; (2) To discover how the allantois and embryo collaborate to build the umbilical cord; (3) To discover the mechanism by which the umbilical and embryonic vasculatures become continuous; (4) To discover the role of the ACD in formation of the embryonic hindgut; and (5) To discover the functional relationship between the ACD, the umbilical cord, and formation of posterior fetal organs, using mouse mutants heterozygous for the Brachyury mutation as our model system. ? ? Project Narrative: We will investigate the function of a new architectural element of the murine allantois, precursor of the umbilical cord, which is one of two major components of the placenta. This novel element, called the Allantoic Core Domain, or ACD, contains most of the information necessary to generate a complete umbilical cord. If the ACD is absent, the allantois forms a short umbilical stump that exhibits disorganized blood vessels; as a consequence, it does not bridge the maternal circulation with that of its fetus. It is anticipated that understanding this essential umbilical feature will shed light on a number of embryonic birth defects, many of which are correlated with defects in the placenta, specifically its umbilical blood vessels. ? ? ?
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