The goal of this new research proposal is to discover the role of tissue fusion in cell growth, differentiation, and death during morphogenesis of the murine placenta. Although generally ignored in developmental studies as it is nearly always discarded at birth, a healthy and normally functioning placenta is essential in preventing birth defects in the fetus and long-term medical problems in adults. This is not surprising, as the placenta is the fetus' lifeline to its mother, wholly dependent upon her entire physiology for survival. Despite the placentas pre-eminence in fetal health and well-being, how the placenta is formed is a seriously understudied area of embryology. Like that of humans, the chorio-allantoic placenta is composed of two major structures: the umbilicus and the chorionic disk. In the mouse, these are formed by union between three tissues initially well separated in the conceptus. The allantois will unite with the chorion, forming the umbilical component of the placenta, and the chorion unites with the ectoplacental cone, forming the chorionic disk. The mature umbilicus carries fetal blood to and from the chorionic disk, whilst the disk mediates exchange of nutrients, wastes and gases with the mother. Little is known about how union occurs. Mine is one of few laboratories world-wide engaged in the study of early murine placentation. We have begun to elucidate developmental mechanisms involved in chorio-allantoic union, demonstrating that union is dependent upon the developmental maturity of the allantois whereas the chorion is always receptive to fusion with a suitably mature allantois. Moreover, chorio-allantoic union occurs in three major steps, which include transient contact, enduring fusion, and breakdown of the fusing surfaces, which facilitates penetration of the nascent allantoic vasculature into the chorion. Several other groups have demonstrated that two molecules, Vascular Cell Adhesion Molecule (VCAM-1) and its counter-receptor, a4-integrin, are both required for fusion. In accordance with our results of microsurgery in living embryos, we showed that VCAM-1 is gradually expressed in the allantois whilst alpha4-integrin is expressed constitutively on the chorion. In this proposal, we will discover the role of chorio-allantoic and chorio-ectoplacental union in growth, death, and differentiation of the nascent chorio-allantoic placenta.
In Specific Aim 1, the cellular nature, fate of cells, and cell death during chorio-allantoic union, will be discovered.
In Specific Aim 2, the specific fate, cell-cell interactions, and molecular relationships during chorio-allantoic union will be identified.
In Specific Aim 3, how the chorion and the ectoplacental cone unite to form the chorionic disk will be investigated.
In Specific Aim 4, the cellular and molecular defects of the VCAM-1 and a4-integrin mutants will be elucidated.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Reproductive Biology Study Section (REB)
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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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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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