Biomedical subjects

James C Cross

Publications and source records attributed to James C Cross.

25 records · Page 2Linked to original sources

PubMed2003

Differential expression of angiogenic and vasodilatory factors by invasive trophoblast giant cells depending on depth of invasion.

The uterine bed undergoes remarkable changes during pregnancy, including proliferation and decidualization of the uterine stroma and remodeling and angiogenesis of the maternal vasculature. Fetal-derived trophoblast giant cells invade into the uterus where they gain access to the maternal blood circulation to ensure sufficient nutrient supply of the embryo. In serial sections through early- to mid-gestation conceptuses, we have determined the exact distance of trophoblast invasion and the expression of angiogenic, vasodilatory, and anticoagulative factors that are likely to influence remodeling and redirection of the maternal circulatory system. Trophoblast derivatives were detected at a distance as far as approximately 300 microm from the placental border, where they are allocated exclusively along the mid-line of the decidua. The farthest invading cells characteristically expressed proliferin and proliferin-related protein, hormones that affect endothelial cell migration and vascularization. Occasionally, these cells replaced the normal vascular endothelium and acquired a "pseudo-endothelial" shape. Complete vascular disintegration was observed 50-80 microm outside of the placental border where maternal blood was entirely lined by a trophoblast giant cell-derived network of blood sinuses. This transition in blood space lining correlated with trophoblast expression of various vasodilatory and anticoagulative factors that are likely to promote blood flow toward the placenta. Analysis of teratocarcinoma-like tumors demonstrated that trophoblast giant cell-induced promotion and redirection of blood flow is not restricted to the uterine environment. These results show that trophoblast giant cells have the intrinsic capacity to attract and increase blood flow and to gradually displace the vascular endothelium resulting in the formation of canals entirely lined by trophoblast cells.

Animals↗

PubMed2003

Chorioallantoic morphogenesis and formation of the placental villous tree.

The placenta is a highly specialized organ whose primary function is to promote the exchange of nutrients and oxygen between maternal and fetal blood, essential for survival and growth of the baby. The surface area for nutrient transport is a highly convoluted villous structure that forms by branching morphogenesis. In mice, this process begins after embryonic day 8.5, following attachment of allantoic mesoderm to the chorion, and continues through the end of gestation. Gene targeting studies in mice have identified a large number of genes that are essential for chorioallantoic development to give rise to the layer of the placenta called the labyrinth. Collectively, these studies reveal that a number of signaling pathways regulate four distinct phases of labyrinth development: chorioallantoic attachment (involving VCAM1 and its receptor alpha4 integrin, Bmp5/7, and Wnt7b, as well as the cochaperone Mrj), initiation of branching (involving the Gcm1 transcription factor to select sites of branch initiation), extension of villous branching (involving FGF, EGF, and HGF/Met signaling, through the Grb2/Sos1/Mek1/p38alpha MAPK pathway), followed by vascularization of the villous tree. The restricted expression and/or action of the signaling components indicate that a series of intercellular interactions regulate chorioallantoic development.

Allantois↗

PubMed2003

Interferon-stimulated gene-15 (Isg15) expression is up-regulated in the mouse uterus in response to the implanting conceptus.

An early response of the human and bovine endometrium to pregnancy is induction of an interferon (IFN)-stimulated gene (ISG) that encodes the ubiquitin-related protein, ISG15. Because the mode of implantation differs among species, we tested whether Isg15 mRNA was also expressed in the mouse uterus in response to the implanting conceptus. Isg15 mRNA was detected in the mouse uterus and increased after d 4.5 of pregnancy but did not change between d 3.5 and 9.5 of pseudopregnancy. Within the decidua, Isg15 mRNA was localized to the antimesometrial zone of the implantation sites. The level of Isg15 mRNA in artificially induced deciduomas was similar to the nonpregnant uterus and was approximately 10-fold lower than in the pregnant uterus. In vitro, murine decidual cells derived from artificially induced deciduomas could be induced to produce the Isg15 protein as well as Isg15-conjugated proteins when stimulated with type 1 IFN, though were less responsive to IFN-gamma. Isg15 is one of few gene products identified in murine implantation sites to require presence of the conceptus and not simply differentiation of the stroma. In vitro data support the inference that the pregnancy-specific inducer of uterine Isg15 is a type 1 IFN or a cytokine that signals through a similar pathway.

Animals↗

PubMed2002

Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta.

Mammalian embryos have an intimate relationship with their mothers, particularly with the placental vasculature from which embryos obtain nutrients essential for growth. It is an interesting vascular bed because maternal vessel number and diameter change dramatically during gestation and, in rodents and primates, the terminal blood space becomes lined by placental trophoblast cells rather than endothelial cells. Molecular genetic studies in mice aimed at identifying potential regulators of these processes have been hampered by lack of understanding of the anatomy of the vascular spaces in the placenta and the general nature of maternal-fetal vascular interactions. To address this problem, we examined the anatomy of the mouse placenta by preparing plastic vascular casts and serial histological sections of implantation sites from embryonic day (E) 10.5 to term. We found that each radial artery carrying maternal blood into the uterus branched into 5-10 dilated spiral arteries located within the metrial triangle, populated by uterine natural killer (uNK) cells, and the decidua basalis. The endothelial-lined spiral arteries converged together at the trophoblast giant cell layer and emptied into a few straight, trophoblast-lined "canals" that carried maternal blood to the base of the placenta. Maternal blood then percolated back through the intervillous space of the labyrinth toward the maternal side of the placenta in a direction that is countercurrent to the direction of the fetal capillary blood flow. Trophoblast cells were found invading the uterus in two patterns. Large cells that expressed the trophoblast giant cell-specific gene Plf (encoding Proliferin) invaded during the early postimplantation period in a pattern tightly associated with spiral arteries. These peri/endovascular trophoblast were detected only approximately 150-300 microm upstream of the main giant cell layer. A second type of widespread interstitial invasion in the decidua basalis by glycogen trophoblast cells was detected after E12.5. These cells did not express Plf, but rather expressed the spongiotrophoblast-specific gene Tpbp. Dilation of the spiral arteries was obvious between E10.5 and E14.5 and was associated with a lack of elastic lamina and smooth muscle cells. These features were apparent even in the metrial triangle, a site far away from the invading trophoblast cells. By contrast, the transition from endothelium-lined artery to trophoblast-lined (hemochorial) blood space was associated with trophoblast giant cells. Moreover, the shaping of the maternal blood spaces within the labyrinth was dependent on chorioallantoic morphogenesis and therefore disrupted in Gcm1 mutants. These studies provide important insights into how the fetoplacental unit interacts with the maternal intrauterine vascular system during pregnancy in mice.

Animals↗

PubMed2002

A differential screen for putative targets of the bHLH transcription factor Hand1 in cardiac morphogenesis.

The bHLH transcription factor, Hand1 has been implicated in cardiac looping in the mouse, however its function in the developing heart remains unknown. To investigate the mechanism(s) through which Hand1 might function, we screened for potential downstream target genes using representational difference analysis. Thymosin beta4 was found to be down-regulated whereas cystatin C and alphaCA were up-regulated in Hand1-null embryoid bodies. Whole-mount in situ hybridisation on wild type embryos (E8.0-E10.5) and Hand1 homozygous-mutant embryos (E8.0) confirmed co-expression of the putative targets with Hand1 in the heart and their aberrant expression in a Hand1-null background.

Basic Helix-Loop-Helix Proteins↗

PubMed2002

A differential screen for putative targets of the bHLH transcription factor Hand1 in cardiac morphogenesis.

Animals↗

PubMed2002

Transcription factors underlying the development and endocrine functions of the placenta.

The placenta has been the subject of extensive basic research efforts in two distinct fields. The developmental biology of placenta has been studied because it is the first organ to develop during embryogenesis and because a number of different gene mutations in mice result in embryonic lethality due to placental defects. The trophoblast cell lineage is relatively simple such that only two major, terminally differentiated cell types appear: an "invasive trophoblast" cell subtype such as extravillous cytotrophoblast cells in humans and trophoblast giant cells in mice, and a "transport trophoblast" cell subtype that is a syncytium (syncytiotrophoblast) in humans and mice. These two cell types also have been the focus of endocrinologists because they are the source of major placental hormones. Understanding the transcriptional regulation of placental hormone genes has given insights into the control of specificity of gene expression. Because most placental hormones are produced by very specific trophoblast cell subtypes, the transcriptional details promise to give insights into cell-subtype specification. The fields of developmental biology and molecular endocrinology appear to be meeting on this common ground with the recent discovery of key transcription factors. Specifically, the basic helix-loop-helix (bHLH) transcription factor Hand1 is essential for differentiation of trophoblast giant cells in mice and also regulates the promoter for the giant cell-specific hormone, placental lactogen I gene (Pl1). In contrast, formation of syncytiotrophoblast cells in mice is controlled by a distinct genetic pathway that is governed by the Gcm1 transcription factor, a homologue of the Drosophila glial cells missing gene. Human GCM I has been shown to regulate the activity of the placental-specific enhancer of the aromatase gene (CYP19), which is specifically expressed in syncytiotrophoblast. Together, these findings imply that some key transcription factors have the dual functions of controlling both critical cell fate decisions in the trophoblast cell lineage and later the transcription of cell subtype-specific genes unrelated to development.

Animals↗