(Domestic, Laboratory) Mouse
1) General zoological data of species
This chapter is written primarily for those pathologists and investigators who find the complex placenta of rodents very difficult to understand. Because of this, essential parts of the mouse gestational sac have occasionally been discarded inadvertently. An example is the membranous dome (the inverted yolk sac placenta) through which there is much transport of various substances. Such tissues should always be included when murine experimental studies are conducted. This applies especially to studies that investigate embryonic growth, exposure to pathogens and other substances such as immunoglobulins. The chapter, therefore, differs in its composition and is more richly illustrated.
Mice are distributed worldwide. There are many different species, which often, but not always, have different chromosome numbers (2n = 22-40). Numerous breeding colonies exist in most laboratories. This is especially so for the Bar Harbor Laboratories in Maine, with the largest experience in genetic diseases and various anomalies.
General gestational data
|C57/Bl/6 mouse (Courtesy Dr. E. Masliah).|
|Swiss Webster albino mouse - 13 dpc.|
The implantation of most rodents, including that of the mouse, occurs initially antimesometrially, with the embryonic disk occupying a mesometrial location. It is a superficially invasive placenta (it is "interstitial"), with a "folding" type of amniogenesis. The major portion of the placenta becomes discoid and has both - a larger labyrinthine (hemochorial) structure - and a smaller region, the trophospongium. Both of these areas are especially confusing. In addition to these two areas, there is the portion of the gestational sac represented by the inverted yolk sac. It forms the dome of the gestational sac. Most mouse placentas are separated one from another, even when they were "stuffed" into uterine horns with the intent of causing chimerism. Heinecke & Grimm (1971), however, reported that fusion did occur in a very small number of implantations, perhaps as a result of damage to blastocyst or endometrium.
All these structures are substantially different. In early stages, the yolk sac is well developed. Later, however, it becomes inverted, so that its endodermal epithelial layer comes to lie opposite the endometrium on the uterine wall. The conceptus' membranous sac, lying opposite to the disk, thus becomes the "visceral yolk sac placenta".
In the early stages of the developing mouse blastocyst, the trophectoderm represents the major portion (70-80% of cells) of the future conceptus. A smaller number of inner cells (the currently much debated "stem cells") that represent the future fetus, lies within the blastocyst. The initial attachment of the blastocyst, which is derived from the trophectoderm - the "mural" trophectoderm, occurs when trophoblast invades the endometrium.The implanting blastocyst is then still positioned deep in an endometrial crypt. This proliferating trophoblast forms a "cone" herein that is often referred to as the "Träger" (= carrier). When the opening of the endometrial crypt closes this area becomes the egg chamber ("Eikammer").
The blastocyst, with its proliferating trophoblast, now assumes a more cylindrical shape. The initial attaching trophoblast cells proliferate from the bottom of the cone as a modification or extension of the träger. (Please see the explanatory diagram to follow - mural trophectoderm). During this early stage, the embryonic yolk sac makes up another dominant portion of the developing embryonic tissues. Later, this yolk sac membrane becomes totally inverted, so that its epithelium presses against the endometrial mucosa at the dome of the cavity. . It has recently been shown that fibrinogen is essential for the successful attachment the blastocyst and maintenance of placentation (Iwaki et al., 2002). Mice deficient in the FG-? chain consistently aborted.
The placental disk now lies on the opposite (mesometrial) side of the uterus. Although there is no allantoic sac in mice, some of the initially present allantoic tissues provide the stalk for the development of the umbilical cord. The early fusion of the allantoic and chorionic murine membranes has now been studied in some detail by Downs (2002). The fusion process appears to be highly regulated through the attractions of the adhesion molecule VCAM-1 in the allantois and a4-integrin in the chorion. After fusion the remaining barrier is broken down, and thus, the body stalk develops. In comparing the development of different mouse strains, Dickson (1967) found that blastocysts do not always develop equally well and also, that their development is not necessarily synchronous. Recent research has identified a variety of genes that are responsible for implantation, adhesion, endocrine response, and so forth. They are summarized by Giudice (1999).
|Early stages of mouse development. Colors of text refer to these colors.|
As was indicated at the beginning of this chapter, the anatomy of the mouse placenta is very complex. Rossant & Croy (1985) used reconstituted embryos to determine which cells of the placenta are of maternal origin, which are fetal and, of these, which originate from the embryonic disk and which come from the trophectoderm. Cross et al. (1994) provided some initial comparisons of mouse and human implantation and detailed the molecular basis for the interactions of the maternal and fetal organisms.
A major publication by Georgiades et al. (2002) presents much more detailed information on the cellular composition of the placental disk and on the implantation site. It endeavors especially to compare the various cell types of mouse trophoblast with those found in the human placenta. The original publication must be consulted for this detail. Likewise, the review by Rossant & Cross (2001)provides evidence that extensive signaling occurs between trophoblast and embryonic cells which, when disrupted, may lead to abortion or embryonic maldevelopment. Cross (2000a) has given further emphasis to the notion that the mouse placentation is a useful model to understand the less-accessible (genetically speaking) human placentation.
The ectoplacental cone and the extraembryonic ectoderm of the primitive streak stage are derived from the trophectoderm. These experiments showed that, when the placental portions were divided into labyrinthine and spongiotrophoblastic components, the maternal contributions were essentially confined to the latter segments. Most of the decidual tissue was maternal in origin but there was also a minor fetal tissue contamination (i.e. the trophoblastic giant cells). About 30% of the cells in the placental disk derive from maternal tissues. They are largely confined to the spongiotrophoblast region. The cellular components of the inner cell mass, which is largely confined to the placental labyrinth, constitute only about 4%. The analysis was somewhat hampered by the presence of contaminating blood cells but are the best approximations available. These are difficult experiments. It should also be mentioned that not all placentas of reconstituted embryos were identically admixed. Hence, not surprisingly, other investigators had somewhat different findings
The giant cells of the rodent placenta have presented a special topic of study for many investigators. These cells, which form the primary site of attachment to the endometrium, can be grown in vitro (Copp, 1980). Their development begins at the abembryonic pole of trophoblast and then spreads towards the embryo (+/- 4dpc). During the first half of development, 10-30% of trophoblastic cells contain giant nuclei that have large quantities of DNA. This DNA is derived through the process of endomitosis (chromosomal replication without cell division). By 11 dpc, up to 850 times the normal amount of DNA is found in these nuclei (Barlow & Sherman, 1972; 1974). DNA replication continues unabated throughout gestation (Copp, 1978). Experiments with actinomycin D by Snow & Ansell (1974) indicate that the DNA in these giant cells is actually composed of large numbers of chromosomes. Mitosis does not occur in these cells (Heine, 1976). Dickson (1963) found that, in delayed implantation, fewer of these cells develop.
Not only do these cells accomplish the initial implantation; they also acquire endocrine function (Gardner & Johnson, 1972), immune functions and cytokine production (Cross, 2000b). Ultimately, the giant cells surround the entire membranes. They become the trophospongium, the area of the placental disk located at the "bottom", at the site of implantation and connecting the placenta to the decidua. This tissue is largely composed of giant cells. Its cells are more compacted at the interface between the peripheral giant cell layer and the labyrinth (please see subsequent photo). Through mutational analysis, gene insertion, knockouts, and other modern techniques, we have obtained a much better understanding of the intricate nature of the implantation process and early development (see section on genetics below. Detailed accounts are by Anson-Cartwright et al., 2000; Cross 2000; Luo et al., 1997). Rossant & Cross (2001) have recently summarized this rapidly expanding field.
The placental labyrinth comprises the major portion of the placental disk; it has very thin fetal capillaries that are supported by a miniscule amount of connective tissue. They, in turn, are surrounded by trophoblast. And these are bathed in the maternal sinusoidal blood. This region constitutes the major site of maternal/fetal exchange. The labyrinth forms by much folding of the villous tissues.
The visceral yolk sac placenta, the thin membrane that lies opposite
the placental disk and apposes the peripheral endometrium, is much more
simply constructed. A cylindrical epithelium faces the variably cuboidal
and cylindrical endometrial epithelium, seemingly without having direct
contact; at least this is difficult to ascertain in the sections made
after fixation. Those apparent spaces seen in our routine histologic sections
are artifact. They are caused by fixation-induced tissue shrinkage. The
tissue components are actually contiguous. Important transport of many
substances occurs at this interface. They are different, however, than
those that reach the embryo through the disk. Brambell (1966) showed that
immunoglobulins traverse this barrier from mother to fetus. And since
then, many other substances have been shown to pass this epithelial contact
zone. This transport, however, was primarily investigated in a variety
of other rodents (rat and hamster). While it is true that most
of these studies have been done in hamsters and rats, there is reason
to believe that the same results hold true for mice. Among the substances
studied were viruses, vital dyes, and many other agents administered to
the maternal organism. This is well elaborated by Carpenter & Ferm
(1969) who traced thorotrast across this membrane in the golden hamster.
|Diagrams of early placental development (After Mossman, 1983). Figure 1 is at approximately 7-7 1/2 dpc. Figure 2 is at approximately 8 dpc. Figure 3 is at approximately 10-11 dpc.|
two pregnant uteri are in situ. The top is at 13 days and contains
13 embryos with the defective one leaving a space between 3 and 4 at top
left. The uterine arterial arcade is well displayed.
The bottom uterus is at 18 days and has 10 normal embryos.
|Diagram of mouse implantation at end of gestation (After Mossman, 1983).|
|Implanted placental disks near end of pregnancy. Note the narrow stalk of the maternal vascular supply and the lateral infolding of the yolks sac membrane.|
|Implanted placental disks near end of pregnancy. Note the narrow stalk of the maternal vascular supply and the lateral infolding of the yolks sac membrane.|
|Cross-section of pregnant uterus with fetus inside at 17 dpc.|
|This 18 dpc placental implantation area shows the two layers (I,II) of the trophospongium to which reference is made in the text. A layer of giant cells (GC) invades the decidua beneath, and a large maternal vessel (MV) penetrates into the labyrinth.|
5) Details of barrier structure
Ramsey (1975) described the complex trophoblast development of the mouse thus:
"The trophoblast forming the ectoplacental cone or träger gives rise to three types of trophoblast. The earliest to appear are wandering giant cells that infiltrate the maternal tissue and eventually come in contact with maternal blood vessels which they open up, thereby creating the hemochorial state. These cells appear to be actively phagocytic for the first 10 days of gestation. The second derivative of the träger is syncytiotrophoblast and the final one the cytotrophoblast. These two compose the walls of the labyrinthine tubules."
(She then refers to an electronmicrophotograph showing this triple layer of trophoblast). Thus, the barrier in the disk is, strictly speaking, a hemotrichorial one. This, of course, is in contrast to the visceral yolk sac placental membrane, which is epithelium to epithelium and, despite this seemingly thick barrier, still provides much exchange function.
|The pictures (left and below left) show the 18 dpc placenta implanted and mesometrium at bottom (left). Both show the wider labyrinthine placental portion beneath the chorionic plate, in the middle is the layer of trophospongium, and beneath it the second layer. Giant cells follow beneath with invasion of decidua and (minimally) into the myometrium.|
|The pictures (left and above left) show the 18 dpc placenta implanted and mesometrium at bottom (above left). Both show the wider labyrinthine placental portion beneath the chorionic plate, in the middle is the layer of trophospongium, and beneath it the second layer. Giant cells follow beneath with invasion of decidua and (minimally) into the myometrium.|
|This picture shows the fetal surface portion of the labyrinth.|
|Floor of 18dpc mouse placenta with two regions of trophospongium, decidual invasion by giant cells and myometrium below.|
|High magnification of labyrinthine placental portion. Giant trophoblast forms the surface of the fetal villi. Most of the red blood cells present here are in fetal capillaries; the maternal spaces are mostly empty.|
6) Umbilical cord
The one umbilical cord that I have measured was 1.5 cm long, on day 18 pc. It was very thin and translucent, and arose from the center of the placental disk. It had no spiral turns. The cord was covered by a very thin amnion and lacked Wharton's jelly. The vitelline cord was also extremely thin. It swung around the embryo to reach the thinnest portion of the "membranes" at the dome of the implantation site, opposite the placental disk. The cord had three very thin blood vessels, an artery and two veins.
|Situs at 18 days with placental disk at left and cord remnant. The vitelline vessels course along the membranes to the fundus portion of the inverted yolk sac.|
|These two photographs (left, bottom left) show the edge of the 18 dpc placenta with the insertion of the inverted yolk sac placental membrane shown as a fold (seen as a ring in the macroscopic yellow photo). Note that near the insertion of the yolk sac membrane the endodermal epithelium is folded (villus-like) and much thicker than on top. The endometrium is also much thicker here. The amnion is extremely thin.|
|These two photographs (left, above left) show the edge of the 18 dpc placenta with the insertion of the inverted yolk sac placental membrane shown as a fold (seen as a ring in the macroscopic yellow photo). Note that near the insertion of the yolk sac membrane the endodermal epithelium is folded (villus-like) and much thicker than on top. The endometrium is also much thicker here. The amnion is extremely thin.|
|The umbilical cord is composed of two portions. At the left side is the vitelline segment with one artery and two veins. At right is the allantoic segment (1A, 1V).|
|Cross section of umbilical cord near the abdomen. The left portion is the vitelline circulation (1A, 2V), the right is the allantoic portion (1A, 1V).|
|The picture at left is a section through the main umbilical cord (allantoic). In the picture at the bottom left, the main cord (large vessels) is on the left, while the yolk sac vessels (smaller and here only 2) are on the right.|
|The picture (above left) is a section through the main umbilical cord (allantoic). In the picture to the left, the main cord (large vessels) is on the left, while the yolk sac vessels (smaller and here only 2) are on the right.|
There are initially three vessels in the vitelline portion of the umbilical cord (one artery and two veins). The vessels split on the way to their distribution across the yolk sac membrane. Thus, this part of the cord leads from the umbilicus to the dome of the dilated sac. It ends on the opposite side of the placental disk. The allantoic portion is thicker and contains one artery and one vein. It also leads to the umbilicus. These vessels have a much thicker wall than those of the omphalomesenteric (vitelline) circulation. There are no vitelline or allantoic ducts.
|Two views of the dome of the implantation sac - the "free membranes" as they are attached to the myometrium - 18 dpc. Note the vitelline vessels in the inverted yolk sac membrane, very thin myometrium, and infiltration of myometrium by trophoblastic giant cells (bottom membrane).|
|Higher magnification of peripheral membranes on day 18 pc.|
|The membranes of adjacent mouse embryo placentas may be intimately fused, even though their placentas remain separate.|
|Maternal blood vessel in the decidua (top left), partially replaced by giant cells (GC) that are also seen below the blood vessel.|
spongiotrophoblast (giant cells), that opened the maternal blood vessels,
is intermixed with decidual cells. This trophoblast, however, does not penetrate
deeply into the myometrium. There is some degree of alteration of the maternal
arteriolar walls by trophoblastic (giant cell) ingrowth with partial replacement
of the muscular wall. This is a common feature of human gestation, but it
is much more pronounced in their placentation.
additional progress has been made in understanding the impact certain
genes make on mouse placental development. Thus, the imprinted Esx1
mutational segment of the mouse homeobox complex is imprinted and, when
inherited from the mother, has destructive effect on the placental labyrinth
(li & Behringer, 1998). Much other work with mice has led to a better
understanding of human conditions and the regulation of the placenta.
For instance, the work by Sun et al (1997) with the insertion of the transgene
for IFG2 leads to Beckwith-Wiedemann-like syndromes. The topic is too
extensive, and it is too rapidly moving for a comprehensive discussion
here. It has recently been aptly summarized by Rossant & Cross (2001).
|In one of the uteri dissected, one embryo had died in utero and only remnants of placenta and embryo remained in a mostly empty cavity. These are representative views of the empty cavity, degenerating placenta and embryo. This may well have been due to a chromosomal error.|
twins with shared yolk sacs and shared circulation were described by Runner
(1984). A plethora of diseases of mice and congenital anomalies have been
reported, but there are too many studies to be covered in this context.
The reader is referred to two comprehensive reviews (Benirschke et al.,
1978; Knobil & Neill, 1998).
Other relevant features
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