Department of Biochemistry and Molecular Biology; University of Calgary
The normal mature placenta in mice is comprised of three major layers: an outer layer of trophoblast giant cells that function in altering maternal physiological functions, a junctional zone called spongiotrophoblast, and an inner "labyrinth" of densely packed villi that are composed of an outer trophoblast layer and inner core of blood vessels. Later in development, spongiotrophoblast cells differentiate into glycogen trophoblast cells. Interest in the placenta has been invigorated by the discovery that several imprinted genes control its development and more recently by the discovery that attempts to clone animals are often complicated by defects in the placenta. While it has been tempting to assume a simple common mechanism, as investigators have examined the underlying pathologies, it is clear that cloning and the various imprinted genes contribute to different types of placental dysplasia: in p57Kip2 mutants, the labyrinth is hyperplastic; in Mash2 mutants, the spongiotrophoblast is lost; in IGF-II mutants, glycogen trophoblast cells are reduced; in placentas from cloned mice, the spongiotrophoblast layer is larger. Interpreting these changes in placental growth patterns is difficult because the mechanisms controlling placental development have been poorly understood. Recent work, however, has unraveled a number of key principles that should advance our thinking. 1) Proliferation of trophoblast stem (TS) cells early in development is stimulated by fibroblast growth factor (FGF) expressed in a spatially-restricted manner by cells of the embryonic ectoderm; 2) The transcription factors Hand1 and Gcml promote differentiation of TS cells into giant cells and the labyrinth, respectively, and their expression is tightly restricted to repress activity in TS cells; 3) Trophoblast cells also show limited FGF-independent proliferation that is enhanced by Mash2, implying that the spongiotrophoblast proliferates but only transiently; 4) Although the placenta continues to enlarge until term, the ability to isolate TS cells from the placenta declines after E8.5. However, in Rb and p57Kip2 mutants, TS cells persist and the labyrinth is dysplastic; 5) Primary growth of the labyrinth is due to branching morphogenesis of the chorioallantoic interface and vascularization is secondary. As suggested by Esxl mutants, increasing placental surface area through more branching may compensate for reduced vascularity; 6) FGF regulates both TS cell proliferation and branching morphogenesis in the labyrinth, though the two functions are attributable to distinct downstream signal transduction cascades. (Supported by the Canadian Institutes of Health Research).