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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-H (02))
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Ilekis, John V
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University of Wisconsin Madison
Anatomy/Cell Biology
Schools of Medicine
United States
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Nelson, Daryl O; Lalit, Pratik A; Biermann, Mitch et al. (2016) Irx4 Marks a Multipotent, Ventricular-Specific Progenitor Cell. Stem Cells 34:2875-2888
Lalit, Pratik A; Salick, Max R; Nelson, Daryl O et al. (2016) Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors. Cell Stem Cell 18:354-67
Wolfe, Adam D; Downs, Karen M (2014) Mixl1 localizes to putative axial stem cell reservoirs and their posterior descendants in the mouse embryo. Gene Expr Patterns 15:8-20
Mikedis, Maria M; Downs, Karen M (2014) Mouse primordial germ cells: a reappraisal. Int Rev Cell Mol Biol 309:1-57
Mikedis, Maria M; Downs, Karen M (2013) Widespread but tissue-specific patterns of interferon-induced transmembrane protein 3 (IFITM3, FRAGILIS, MIL-1) in the mouse gastrula. Gene Expr Patterns 13:225-39
Mikedis, Maria M; Downs, Karen M (2012) STELLA-positive subregions of the primitive streak contribute to posterior tissues of the mouse gastrula. Dev Biol 363:201-18
Daane, Jacob M; Downs, Karen M (2011) Hedgehog signaling in the posterior region of the mouse gastrula suggests manifold roles in the fetal-umbilical connection and posterior morphogenesis. Dev Dyn 240:2175-93
Downs, Karen M (2011) Lineage Commitments: Emphasis On Embryonic-Extraembryonic Interfaces. EMBO Rep 12:987-90
Daane, Jacob M; Enders, Allen C; Downs, Karen M (2011) Mesothelium of the murine allantois exhibits distinct regional properties. J Morphol 272:536-56
Zaitoun, Ismail; Downs, Karen M; Rosa, Guilherme J M et al. (2010) Upregulation of imprinted genes in mice: an insight into the intensity of gene expression and the evolution of genomic imprinting. Epigenetics 5:149-58

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