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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD042706-06
Application #
7386891
Study Section
Special Emphasis Panel (ZRG1-EMNR-H (02))
Program Officer
Ilekis, John V
Project Start
2002-07-01
Project End
2013-01-31
Budget Start
2008-02-15
Budget End
2009-01-31
Support Year
6
Fiscal Year
2008
Total Cost
$309,179
Indirect Cost
Name
University of Wisconsin Madison
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Rodriguez, Adriana M; Jin, Dexter X; Wolfe, Adam D et al. (2017) Brachyury drives formation of a distinct vascular branchpoint critical for fetal-placental arterial union in the mouse gastrula. Dev Biol 425:208-222
Rodriguez, Adriana M; Downs, Karen M (2017) Visceral endoderm and the primitive streak interact to build the fetal-placental interface of the mouse gastrula. Dev Biol 432:98-124
Wolfe, Adam D; Rodriguez, Adriana M; Downs, Karen M (2017) STELLA collaborates in distinct mesendodermal cell subpopulations at the fetal-placental interface in the mouse gastrula. Dev Biol 425:44-57
Lalit, Pratik A; Rodriguez, Adriana M; Downs, Karen M et al. (2017) Generation of multipotent induced cardiac progenitor cells from mouse fibroblasts and potency testing in ex vivo mouse embryos. Nat Protoc 12:1029-1054
Mikedis, Maria M; Downs, Karen M (2017) PRDM1/BLIMP1 is widely distributed to the nascent fetal-placental interface in the mouse gastrula. Dev Dyn 246:50-71
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

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