2) General gestational data

The length of gestation in the mouse generally is 19 days, with the developmental stages often referred to as being: "xx dpc" (= xx days post coitum). Litter size in mice varies from 4 to 12 embryos. Occasionally, because of a fetal demise, an empty space is found in the typically bicornuate uterus. The white mice used for these pages were of the following weights: at 14 days pregnant - 38 g, after removal of uterus - 30 g; at 18 days pregnant - 57 g, after removal of the uterus - 34 g. The 18-day mouse fetus weighed 1.8 g with placenta and measured 2 cm in length with the placental disk measuring 2 x 0.6 cm. It had a 1.5 cm long umbilical cord.

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).

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.

This membrane of visceral yolk sac inserts in a ring-like fashion on the surface of the disk (please see below). It has a much more prominent, folded epithelium near the disk, and becomes thinner and thinner as it stretches around the embryo to the dome of the uterine wall.

7) Uteroplacental circulation

The principal maternal vessels enter in the center of the ovoid disk. The arteriolar walls of the maternal vessels are modified by ingrowth of trophoblast. The veins are large and thin-walled, without trophoblast. Large maternal blood channels are situated deep in the labyrinthine tissue whence they divide to make the complex sinusoidal path along the villous surface. They then contact trophoblast.

Cross et al. (2001) have studied the vascularization of the mouse placenta with vascular casts. They suggested that the uterine NK cells are vital in establishing the vascular bed and that much of the vascular development depends on the activity of the giant cells. They found that the uterine artery branches into several spiral arteries. These vessels lack smooth muscle and converge at the junction to the giant cells. Here they open into the trophoblast-lined canals that enter the labyrinth. Mossman (1987) has diagrammed this complex blood flow.

8) Extraplacental membranes

There is no decidua capsularis. The membranous portion of the implanted mouse pregnancy is, sequentially identified from the outside inwards, composed of as follows: Peritoneum, myometrium, thin layer of endometrium, space with some secretion, yolk sac epithelium, connective tissue layer of inverted yolk sac membrane with a few vitelline vessels, amnionic connective tissue, and a very thin amnionic epithelium (which is usually shriveled up in sections). There is no allantoic sac.

10) Endometrium

There is a marked decidual reaction of the mouse endometrium (which can also be stimulated to develop merely by physical manipulation and also through hormonal manipulation). The decidualization does not include the entire endometrium, however, as will be seen from the photographs of the membranes. At the periphery of the decidual reaction, much glycogen is found in the decidual cells. Capillaries invade this region, and these become subsequently much larger. Finn & Lawn (1967) studied the decidual cells ultrastructurally and identified tight junctions between the cells.

11) Various features

There is no well-developed subplacenta in the mouse but, as can be seen in the center of the discoid placentas here depicted, a suggestion of a subplacenta forms.

12) Endocrinology

The estrous cycle of mice is 3-9 days long. Endocrine aspects of mouse gestation are complex; they have been comprehensively reviewed by Birken et al. (1998). During the early part of gestation, LH stimulates luteal androgen production that is converted to estradiol. This, in turn, stimulates progesterone secretion until midgestation. The placenta then secretes androgens for maintenance of pregnancy, this being referred to as the "luteal shift". When fetectomy is performed, androgen secretion falls dramatically. The placental histologic integrity remains intact, however. It is still unknown if a chorionic gonadotropin exists. Good evidence has been provided by Gardner & Johnson (1972) of hormone production by the trophoblastic giant cells. In paragraphs of "Genetics" below and from Giudice (1999), the reader will find the various genetic factors that are needed for progesterone production and implantation.

13) Genetics

Mice generally have 40 chromosomes, all being acrocentric elements (Committee, 1972). A common finding in mice (as well as some other taxa) is the frequent "Robertsonian fusion" of chromosomes at their centromeres ("whole arm translocation") that reduces the chromosome number, without loss of DNA (Castiglia & Capanna, 1999). There is a huge literature on this topic alone, which commenced with Gropp (review in Gropp et al., 1982; 1983) who identified the low number of chromosomes in Apennine mice (initially the Tobacco mouse, Mus poschiavini 2n=26).

Nesbit (1974) found a 40% banding homology between rat and mouse chromosomes. Although a few reports on mouse hybrids with rats have been issued, they are probably invalid. On the other hand, many different mouse species have hybridized, some with fertility, others with failure. The experiments of hybridization with Mus caroli are especially interesting (Rossant et al., 1983). Only when inner cell mass exchange was done did this lead to the production of heterospecific offspring. Gray (1972) has summarized the extensive literature on mouse hybrids.

Shaver & Martin-DeLeon (1975) reviewed the effect of aging germ cell components. Triploidy, mosaicism and structural anomalies resulted in 2.6% of blastocysts recovered after superovulation. Equally interesting is the study by Yuan et al. (2002) that identifies a synaptonemal complex protein3 gene (SCP3) that functions to allow synapsis of chromosomes at meiosis. In its absence, malsegregation of chromosomes occurs and its absence in mice leads to resorptions, even more so in older mice.

Comprehensive genetic investigations of mice have led to abundant information of their genes. Its genetic structure is now known. There is an abundant literature that cannot be reviewed here. Some of these topics are covered comprehensively by Knobil & Neill (1998). ). How it is possible to localize specific genes and identify the chromosomal location of such a gene by FISH is nicely shown for the X-linked Arhgef6 gene in the contribution by Kutsche & Gal (2001).

The understanding of the major histocompatibility gene complex (MHC) is perhaps most relevant here in view of the problems that occurred in the hybridization experiments of Mus musculus and Mus caroli. The exchange of ICMs succeeded, but the trophoblast was apparently "recognized" and rejected (Rossant et al., 1983). Gill et al. (1983) have reviewed the MHC state of affairs. Hybrids between Mus musculus and Mus caroli were also studied by West et al. (1978) and were found to be sterile. A variety of genetic markers and their expression was explored in this system. The process of imprinting seems to be related to genes located on chromosome 12 and, when the maternal and paternal chromosome are identical, imprinting does not occur, and the mice succumb, with many anomalies and placentomegaly (Georgiades et al., 2001).

Much 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).

Chimerism in mice has been the object of intense study by Tarkowski and later by Mintz (reviewed by Benirschke, 1970). This has have led to much insight into the lineage of cells during development. These topics, however, are beyond the scope of the chapter. Douarin & McLaren (1984) have reviewed the fate of chimeric XX cells in male testes (they vanish). Since mice bear large litters and because numerous corpora lutea can be identified, the question of whether monozygotic ("identical") twins also exist among the litters has often been asked. Wallace & Williams (1965) believed that MZ twins occur as often as 1:100 offspring. They can certainly be produced experimentally by manipulating early stages of development (Sotomaru et al., 1998; Tarkowski et al. 2001). Both these investigative groups of investigators placed single blastomeres into tetraploid carrier embryos and obtained survival under a variety of circumstances, and production of several sets of MZ twins. The investigators successfully made other manipulations that resulted in twins. Kaufman (1982) even produced a set of monoamnionic twins from parthenotes.

McLaren et al. (1995) attempted to identify MZ twins in 200 mice by genetic analysis, but they were unable to find any with certainty. They suggested, therefore, that MZ twinning must be rare. The topic is currently of interest as an increased number of MZ twins accompany the multiples conceived by human infertility therapy. One important question is whether they are the result of embryo handling. Therefore, Cohen & Feldberg (1991) attempted (and succeeded) to show that drilling variable-sized holes into the zona pellucida of mice may lead to premature hatching of blastomeres.

Results of recent studies of genetic mutations have shown convincingly that certain molecules are needed for the development of the labyrinth and for the formation of trophoblastic giant cells (Anson-Cartwright et al., 2000). When a mutation of the Gcm1 locus (encoding the transcription factor glial cells missing-1) is coded, there occur lack of trophoblastic adhesion, lack of villous folding into a labyrinth, lack of giant cell formation, and abortion or early death. Conversely, overgrowth of giant cells and poor development of the diploid trophoblast with fetal death at 10.5 dpc occur when there is a mutational lack of the "orphan nuclear ERR- ß receptor (Luo et al., 1997).

Mice with the chromosomal deletion of one X (39,X) are the genetic equivalent of the human Turner's syndrome. In contrast to the latter, these mice have normal oocytes and may be fertile. Many other chromosomal anomalies (trisomies, XXY, mosaics, chimeras, etc.) have been described. Takagi & Sasaki (1975) showed that the extraembryonic membranes of mice have preferential paternal X-inactivation.

In view of the interest of genomic imprinting (paternal - placenta; maternal - embryo) the study by Ito et al. (1988) is of interest. They were able to follow labeled paternal DNA strands into both, embryo and trophectoderm. Sun et al. (1997) developed a mouse model to study the human Beckwith-Wiedemann syndrome. They introduced the transgene Igf2 (that is responsible for the syndrome's features) with embryonic stem cells. While most of the features of the human syndrome were replicated in the mouse model, some were not (protruding tongue, omphalocele). Nevertheless, this, as well as many similar studies help clarify specific aspects of human maldevelopment that have so far been difficult to access.

14) Immunology

For work on MHC molecules, see Gill et al. (1983). Polyoma virus infection stimulates mouse trophoblastic growth but it does not lead to choriocarcinoma (Koren et al., 1971). One of the most interesting aspects of mouse placentation is the "rejection" of xenotransplanted mouse embryos. When Croy et al. (1982) transplanted blastocysts from Mus caroli into Mus musculus, they initiated a strong inflammatory reaction, hemorrhage and ultimate death of the transplanted embryos. Neighboring Mus musculus embryos and placentas were not affected. It should be pointed out that both species have identical chromosome number with an apparently similar structure. But, when inner cell masses of Mus caroli were placed into the trophectodermal shell of Mus musculus, they developed into normal Mus caroli neonates, supported by the "foreign" placenta. These experiments strongly suggest that, not only is the trophoblast of the foreign genotype immunologically recognized but also, that killer cells of the host destroy the graft. The authors reviewed other interspecific experiments of this kind.

15) Pathological features

Frequently one finds a space in a pregnant mouse uterus that was presumably occupied at an earlier time by an embryo. The reason for its demise are often impossible to discern but with the development of mutant mice and, especially, with the advent of knockout mice and other genetically engineered mice, a better understanding is coming about. Ward & Devor-Henneman (2000) provided for that reason a detailed protocol of how to dissect and assess such fetal deaths. Their chapter is replete with color pictures of the normally developing placenta and membranes and discusses apoptosis in the placenta and various organs and attempts to devise guidelines to differentiate causes of prenatal demise.

One recently identified cause of abortion in mice is the deficient vascular development that results from an absence of a2-adrenoceptors (Philipp et al., 2002). There is a sizeable family of these adreno-receptors; these investigators discriminated among them by knockouts. This particular receptor is beginning to be expressed in the embryo and yolk sac and placenta on day 9.5 and thus, its absence correlated well with the deficient placental vessel development.

16) Physiological data

I have no data or references pertaining to the magnitude of the maternal blood flow, blood volume, or blood pressure of mice.

17) Other resources

Cell lines are available from the Bar Harbor Laboratories and many other agencies. The mouse has been an extraordinary model to study certain genes by the creation of "knockout" mice. There are so many models now available that the topic has become difficult to oversee. For that reason, a "Mouse Knockout & Mutation Database" (MKMD) has been developed in 1995 that now lists over 7000 entries. A sample can be viewed at http://research.bmn.com/mkmd. Ward et al. (2000) published a book on the pathology of genetically engineered mice that may be helpful.

18) Other relevant features

Embryo transfer of mice has been possible since 1935 and is reviewed by Kraemer (1983). This publication also provides references and technical details that may be helpful to the experimenter. Intraspecific chimerae have been produced several times, but the rat x mouse aggregation of blastomeres, while leading to normal appearing blastocysts, did not yield grown chimeric embryos (Stern, 1973). Surani & Barton (1983) produced gynecogenetic embryos, but they failed to go beyond the 25-somite stage. This is presumably due to homozygosity for lethal genes, similar to the androgenetic hydatidiform moles in humans which are lethal to the embryo.


19) Future research needs

There is much information to be gained from the study of mouse placentation. This is especially true for our understanding of the genetic regulation of placentation and trophoblast regulation. The publication by Georgiades et al. (2002) should be consulted for references and directions. In view of the numerous mouse mutations produced, it will be interesting to learn more about the possibly accompanying placental lesions.

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