Axis Development and Early Review Asymmetry in Mammals

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Cell, Vol. 96, 195±209, January 22, 1999, Copyright 1999 by Cell Press Axis Development and Early Review Asymmetry in Mammals Rosa S. P. Beddington* and Elizabeth J. Robertson² is activated and maternal mRNA degraded at the two- *Division of Mammalian Development cell stage, within 24 hr of fertilization. MRC National Institute for Medical Research Cleavage culminates in blastulation when two distinct The Ridgeway tissues form: the trophectoderm (TE) and the inner cell Mill Hill mass (ICM). These are mutually exclusive tissue lin- London NW7 1AA eages, since the progeny of the TE contribute only to the United Kingdom trophoblast and extraembryonic ectoderm and those of ² Department of Molecular and Cellular Biology the ICM to the fetus and extraembryonic mesoderm and Harvard University endoderm (Gardner, 1983). The segregation of these Cambridge, Massachusetts 02138 two tissues is presaged by polarization of individual blastomeres during cleavage, first manifest at the eight- cell stage. A series of asymmetric or symmetric cell divisions ensues that results in segregation of polar Introduction cells, which form the TE, and apolar cells, which form Studying the formation of the embryonic axes in mam- the ICM (Johnson and Ziomek, 1981). Formation of the mals poses a special problem because patterning of the blastocyst gives unequivocal polarity to the conceptus embryo itself is a relatively late event in development. with the ICM situated at one end, which we will call In the mouse, explicit pattern in the tissue that will gener- proximal. More recently it has been confirmed that the ate the future organism only becomes apparent one- nascent blastocyst is also bilaterally symmetrical, being third of the way through a gestational period of 3 weeks. invariably oval rather than spherical (Gardner, 1997). This tardiness of eutherian mammals is due to viviparity. However, this axis of bilateral symmetry does not seem The earliest stages of their development are necessarily to be polarized in that one end cannot be distinguished preoccupied with the generation of extraembryonic tis- from the other (Figure 1, red arrowheads). At 4.5 days, sues essential for survival in utero. This means that the a third tissue differentiates on the surface of the ICM. conceptus, comprising both the extraembryonic and This is the primitive endoderm destined to generate only embryonic components, is already a complex structure the extraembryonic parietal and visceral endoderm and implanted in the uterus by the time the embryo itself (Gardner, 1983). The remainder of the ICM, now known begins to acquire obvious pattern. For this reason, the as epiblast, will give rise to the entire fetus, including architecture of the conceptus as a whole cannot be the germ line and all the extraembryonic mesoderm. ignored when considering the origin of the embryonic Polar TE continues to divide, producing extraembry- axes of mammals. This contrasts with the develop- onic ectoderm that pushes the epiblast and enveloping ment of most invertebrates and anamniote vertebrates, visceral endoderm toward the distal pole of the concep- where, from the moment of fertilization, embryogenesis tus. A cavity forms in the center of the epiblast, due to is wholly concerned with defining the pattern of the a mixture of apoptotic and survival signals from the future organism. Indeed, in many cases, this patterning visceral endoderm (Coucouvanis and Martin, 1995), and begins during oogenesis when molecular asymmetries the epiblast becomes a cup-shaped epithelial tissue. are laid down in the egg. The first morphological sign of embryonic pattern is In this review, we will explore some of the characteris- evident 6.5 days after fertilization when gastrulation tics of mouse development relevant to axis develop- begins. Epiblast cells at one point on the rim of this ment. We will consider whether the pattern that devel- otherwise apparently homogeneous epithelium undergo ops in the mouse conceptus influences pattern that an epithelial±mesenchymal transformation to generate appears later in the embryo, and we will discuss what mesoderm and form the primitive streak. This point de- is known about how the definitive axes of the embryo fines the posterior pole of the future embryo, and, thus, (anterior±posterior [A±P]; dorsal±ventral [D±V]; and left± the diametrically opposite side of the cylinder is recog- right [L±R]) are laid down during mammalian devel- nized as anterior. During the next 12±24 hr, the streak opment. elongates from the rim of the cup to its distal tip. Here, at the anterior end of the streak, a specialized structure forms, which is known as the node (Figure 1). For rea- Anatomy of Early Mouse Development sons given below, the node is considered homologous Figure 1 illustrates the first week of mouse development to the organizer of other vertebrate embryos. The node (see Hogan et al., 1994; Tam and Behringer, 1998, for generates axial mesendoderm, which comprises that more comprehensive review). The fertilized mouse egg mesoderm which will populate the midline of the embryo is a small (approximately 80 mm in diameter) cell. It has (prechordal plate and notochord) and the definitive gut a polarity because the polar bodies generated by the endoderm. Until the node forms, and hence the definitive first and second meiotic divisions are sequentially ex- gut endoderm, the epiblast remains enveloped in extra- truded at the same site, where they remain tethered embryonic visceral endoderm. The posterior end of the during ensuing cleavage (Gardner, 1997). The site of streak gives rise to extraembryonic mesoderm, while their extrusion has been called the animal pole. Although lateral plate mesoderm and paraxial mesoderm emerge cleavage stages are prolonged, taking approximately 3 from the intervening levels of the streak. The midline days for the egg to produce 16 cells, the zygotic genome mesoderm from the node corresponds to what is called Cell 196 Figure 1. Diagram of the First 7.5 Days of Mouse Development from Fertilization Preimplantation development is depicted on the top row with postimplantation development on the bottom (not drawn to scale). The germ layers of the 6.5 and 7.5 day embryos are also shown as flattened sheets for ease of comparison with other vertebrate and mammalian embryos. The major axes of the embryo are shown superimposed on the profile of an adult mouse. dorsal mesoderm in other vertebrates and the extraem- places as fast as every 2 hr (Snow, 1977). Furthermore, bryonic and lateral mesoderm to ventral. Hence, the unlike the predominantly coherent growth seen in pre- origin of the primitive streak is critical in defining not gastrula Xenopus embryos, the epiblast cells of the only the A±P but also the D±V axis. Since the orientation mouse intermix extensively before gastrulation (see be- of the L±R axis is dependent on the orientation of the low). These differences, together with the early activa- other two axes, L±R pattern also ultimately relies on tion of the zygotic genome, early degradation of mater- where the streak forms. Not surprisingly, this morpho- nal mRNA, and the lateness of gastrulation, make it hard logical sequence of events suggested that pattern for- to see how determinants present in the mouse egg could mation in the mammalian embryo could be explained persist long enough directly to influence embryonic pat- once the cues for localizing streak formation were un- tern. However, if embryonic pattern is dictated by the derstood. early axis of bilateral asymmetry in the blastocyst, then It is worth remembering that as well as the presence of it is conceivable that pattern in the fertilized egg could elaborate extraembryonic tissues, mammalian embryos determine the axes of the conceptus and thereby those arrive at gastrulation in a very different state to that of of the embryo. other vertebrate embryos. There is a marked difference in size, there being only about 600 epiblast cells when Axes of the Conceptus gastrulation begins in mouse compared with several In a trivial sense the proximal±distal axis of the blasto- thousand cells in an equivalent stage Xenopus embryo. cyst obviously corresponds to the D±V axis of the em- Presumably because of this, mouse embryos grow rap- bryo (Figure 1). However, this is more of a geometrical idly during the periimplantation period and, unlike Xeno- coincidence than one that has meaning in terms of de- pus, continue to do so throughout gastrulation, epiblast termining pattern formation. As stated above, the D±V cells dividing on average at least every 6 hr and in some axis of the embryo, with respect to where the more Review 197 dorsal tissues of the embryo originate as opposed to has never been tested (see Gardner, 1998). However, ventral ones, is dictated not by the shape of the concep- isolated blastomeres from the two-cell stage can de- tus but rather by where the primitive streak forms. velop into mice, and at later cleavage stages adding, The first intimation that axes of the conceptus might removing, or rearranging cells seems to have no effect influence the orientation of the A±P axis of the embryo on the pattern of the surviving embryos. Such experi- came from histological studies on implanting blasto- ments also indicate that individually cells remain totipo- cysts and early postimplantation egg cylinders (Smith, tent up to the time of blastulation, although their position 1980, 1985). It appeared that the tilt of the 4.5 day blasto- during cleavage will influence their fateÐinside cells cyst was preserved during implantation as a persistent tending to become ICM and outside cells becoming TE bending of the ectoplacental cone to one side (Figure (see Hogan et al., 1994). 1). From these static descriptive studies, it was claimed The strongest argument against graded cues present that this side corresponded to the side on which the in the egg being responsible for dictating the orientation primitive streak would form.

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