1. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; 2. Graduate University of the Chinese Academy of Sciences, Beijing 100039, China
Placenta, a temporary organ first formed during the development of a new life is essential for the survival and growth of the fetus in eutherian mammals. It serves as an interface for the exchange of nutrients, gases and wastes between the maternal and fetal compartments. During the past decades, studies employing gene-engineered mouse mutants have revealed a wide range of signaling molecules governing the trophoblast development and function during placentation under various pathophysiological conditions. Here, we summarize the recent progress with particular respect to the involvement of developmental genes during placentation.
Trophectoderm and its derived extraembryonic ectoderm
Failure of chorioallantoic fusion; Defect of fetal vascular invasion into chorion
Arman et al., 1998; Xu et al., 1998
PLCδ1/PLCδ3
Placenta trophoblast
Reduced vascularization, proliferation and aberrant apoptosis in labyrinth area
Nakamura et al., 2005
Pkbα (Akt1)
Trophoblast giant cell, spongiotrophoblast, labyrinth, the endothelium of fetal capillaries
Small layer of labyrinth and spongiotrophoblast; marked reduction of glycogen-containing cells in spongiotrophoblast; disordered fetal vasculature with fewer vessels
Yang et al., 2003
Gab1
Labyrinth trophoblast cells and spongiotrophoblast Cells
Severely reduced number of trophoblast cells in the labyrinth region
Itoh et al., 2000
Grb2
Unknown
Defects in chorioallantoic fusion, smaller labyrinth structures
Disorganized spongiotrophoblastand labyrinth trophoblast layers, incomplete embryonic vasculature in labyrinth
Qian et al., 2000
B-Raf
Unknown
Discontinuous spongiotrophoblast and giant trophoblast layers, underdeveloped labyrinth layer (hypocellular areas filled with stroma in labyrinth)
Galabova-Kovacs et al., 2006
C-raf-1
Unknown
Reduced size of spongiotrophoblast and the labyrinth layer, poorly vascularized and abundant mesenchymal cells-contained labyrinth layer
Mikula et al., 2001
Mekk3 (Map3k3)
Unknown
Reduced embryonic blood vessels in the labyrinth layer
Yang et al., 2000
Mekk4 (Map3k4)
Labyrinth, spongiotrophoblast, and giant cell layers
A point mutation exhibited dysregulated placental development with increased trophoblast invasion.
Abell et al., 2009
Mek1 (Map2k1)
Labyrinth layer
Less defined spongiotrophoblast layer, more compact labyrinthine region with fewer blood vessels
Giroux et al., 1999; Bissonauth et al., 2006; Nadeau et al., 2009
Erk2 (Mapk1)
Trophoectoderm and its derivatives including ectoplacental cone, extraembryonic ectoderm and giant cells
Failure to form the ectoplacental cone and extraembryonic ectoderm in ERK2 (Ex3) mutants; Thinner labyrinthine layers, few fetal blood vessels penetrating into the labyrinthine layer in Erk2 (Ex2) mutants.
Hatano et al., 2003; Saba-El-Leil et al., 2003
Erk5 (Mapk7)
Labyrinth layer
Thinner labyrinth layer, less intermixing between embryonic and maternal blood vessels in the labyrinthine region, more apoptosis.
Regan et al., 2002; Sohn et al., 2002; Yan et al., 2003
FRS2α
Extraembryonic ectoderm
Trophoblast stem cells failed to maintenance of self-renewing.
Melillo et al., 2001; Gotoh et al., 2005
p38α (Mapk14)
Diploid trophoblast of the placenta, including the labyrinth, yolk sac
Thinner labyrinth layer, greatly reduced spongiotrophoblast,decreased vascular network within the labyrinth layer
Adams et al., 2000; Mudgett et al., 2000
Shp2 (Ptpn11)
Spongiotrophoblast and labyrinth trophoblast (unpublished data)
Diminished numbers of trophoblast giant cells, and failure to yield trophoblast stem (TS) cell lines.
Yang et al., 2006
Tab.1
Fig.2
Gene
Expression in placentas
Placenta phenotype of mutant mice
Reference
Wnt2
Allantois, fetal blood vessels in the labyrinth (unpublished data)
Defects of vascularization in placenta
Monkley et al., 1996
Wnt7b
Chorionic trophoblast
Defects in chorioallantoic attachment and cell organization in chorionic plate
Parr et al., 2001
Fzd5
Labyrinth trophoblast, yolk sac
Small labyrinth, failure of fetal vascular invasion into the chorion, defects in yolk sac angiogenesis
Ishikawa et al., 2001
Tcf1/Lef1
Placenta trophoblast (unpublished data)
Unknown defect in placenta
Galceran et al., 1999
Tab.2
Gene
Expression in placentas
Placenta phenotype of mutant mice
Reference
Jagged 1
Unknown
Died at E10.0 due to the vascular defects.Large blood vessels were not present in the yolk sac.
Xue et al., 1999
Delta-like 4
Trophoblast giant cells, umbilical and vitelline arteries
At E10.5 no viable null embryos were found. Yolk sac defects. Haploid insufficiency leads embryonic lethality. Vascular remodeling defects in the yolk sacs and the major central placenta arteries undergo degeneration and regression.
Duarte et al., 2004; Gale et al., 2004
Notch 1
Vascular endothelial cells in labyrinth, maternal blood sinus (unpublished data)
Single knockout null embryos died before E11.5, but had no placenta defects. Conditional knockout (with tie2-cre) had yolk sac vascular remodeling failure and placenta blood vessels labyrinth invasion defects.
Swiatek et al., 1994; Limbourg et al., 2005
Notch 2
Allantois, spongiotrophoblast, giant cells, endovascular trophoblasts and mesenchymal derivatives in labyrinth
Delayed entry of maternal blood into the mutant placenta and poor blood sinus formation at later stages.
Nakayama et al., 1997; Hamada et al., 1999; Hamada et al., 2007
Notch 4
Vascular endothelial cells in labyrinth
Single knockout exhibited no obvious mutant phenotype. Notch 1 and Notch 4 double knockout had pale yolk sacs, lacking obvious blood vessels and failture of mutant endothelial cells to invade the labyrinth.
Krebs et al., 2000
RBP-J kappa
Mesodermal derivatives in labyrinth
Died before E10.0 due to the deficiency of chorioallantoic fusion.
Oka et al., 1995; Krebs et al., 2004
Hey1 and Hey2
Blood vessels of the allantois and chorionic plate
Complete lack of embryonic blood vessels in the placental labyrinth.
Fischer et al., 2004
Mash2
Ectoplacental cone, chorion and their derivatives in the placenta
Died at E10.0 because of the placental defects. No spongiotrophoblast cells and their precursors, more trophoblast giant cells.
Guillemot et al., 1994; Tanaka et al., 1997
Tab.3
Gene
Expression in placentas
Placenta phenotype of mutant mice
Reference
TGF-β1
Extraembryonic blood islands of the yolk sac, mesodermal cells of the allantois
About 50% homozygous and 25% heterozygous embryos died around E10.5. The yolk sac vasculature defects.
Akhurst et al., 1990; Dickson et al., 1995
Nodal
Spongiotrophoblasts
Insertional null mutant loss of the diploid spongiotrophoblasts and labyrinth, and had more giant cells. Hypomorphic mutation results in an expansion of the giant cell and spongiotrophoblast layers, and a decrease in labyrinthine development.
Iannaccone et al., 1992; Ma et al., 2001
Bmp2
Extraembryonic mesoderm, allantois.
Died at midgestation. Allantois had delayed development.
Winnier et al., 1995
Bmp4
Allantois
Died between E6.5-E9.5. Yolk sac defects, reduced blood islands and no allantois.
Zhang and Bradley, 1996; Lawson et al., 1999
Bmp5and 7
Allantois, endoderm of the visceral yolk sac.
Died at E10.5. Allantois developed abnormal. Failure of chorioallantoic fusion.
Solloway and Robertson, 1999
Bmp8b
Extraembryonic ectoderm.
Short allantois, no allantois in some more severe mutant.
Lawler et al., 1994; Oshima et al., 1996
TGF-β receptorType II
Extraembryonic blood islands of the yolk sac, mesodermal cells of the allantois
Homozygous embryos died around E10.5. Yolk sac hematopoiesis and vasculogenesis.
Ying et al., 2000
Alk1
endothelial cells of fetal vessels
Dilated and fused chorioallantoic vessels.
Lechleider et al., 2001; Tremblay et al., 2001
Smad 1
Yolk sac, allantois
Mutant embryos died around E9.5 due to the defects of allantois formation. The abnormal allantois failed to fuse to the chorion.
Hong et al., 2007
Smad 5
Allantois, yolk sac
Homozygous mutant died between E9.5 and E11.5. Allantois lacked a well-organized vasculature. Allantois could fuse to the chorion, but was not well-elongated.
Chang et al., 1999
P300
Unknown
Null embryos died between E9.0 and E11.5. The yolk sac was poorly vascularized.
Yao et al., 1998
CBP
Unknown
Homozygous embryos died between E9.5 and E10.5. Decreased in erythroid cells and colony-forming cells in the yolk sac.
Oike et al., 1999
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