During development, a single unspecialized cell—the fertilized egg cell—gives rise to cells that are progressively more specialized (this process is known as cell differentiation). But if all nucleated cells in an individual originate from the zygote and have the same set of DNA molecules, how do uncommitted cells in the very early embryo give rise to increasingly specialized lineages of cells? That is, how does differentiation ever arise in the first place? The answer is that epigenetic factors are involved that do not involve changes to the DNA sequence.
Intrinsic and extrinsic asymmetry
Differentiation occurs at an early stage in embryonic development after some asymmetry arises. The cells may have the same DNA molecules but they may nevertheless be different because they have inherited different amounts of fate-determining protein factors (intrinsic asymmetry). Alternatively, they may be exposed to slightly different micro environments and so the extracellular chemical signals received may differ between neighboring cells (extrinsic asymmetry).
In some nonmammalian organisms, intrinsic asymmetry develops in the egg: gradients of certain proteins that are important in early gene regulation can be established in the egg cell (which is a large, sometimes huge, cell). As a result, when the egg undergoes cleavage divisions without cell growth (to give progressively smaller descendent cells), cell division can be asymmetric: one daughter cell receives more of an asymmetrically distributed regulatory protein than the other daughter cell (Figure 1A). One might also consider the potential for asymmetry at fertilization: the sperm entry point (the point at which the sperm makes contact with the egg to inject its nuclear package) might, conceivably, define an axis.
Fig1. Examples of intrinsic and extrinsic asymmetry during early embryonic development. (A) Intrinsic asymmetry. In some organisms the egg is formed with asymmetric localization of certain fate determinants (which may be signaling proteins, specific transcription factors, and so on). In the zygote the asymmetric distribution of the fate determinants (shown here as yellow boxes) will be maintained (being concentrated toward one pole of the zygote). Following cell division (without growth) the daughter cells can have significantly different amounts of the fate determinants. (B) Extrinsic asymmetry. Inner cell A receives chemical signals from neighboring cells on all sides (red arrows). Outer cell B can receive chemical signals from neighboring cells next to it and from beneath it (white arrows) but not from above it.
Extrinsic asymmetry can arise at later stages. As the embryo grows, cells will have different locations. Simply on the basis of their positions in the embryo, cells may be exposed to different local environments, and might differ in the signal inputs they receive from neighboring cells. For example, cells on the outer surface of an embryo can receive signals from cells beneath them, but not above them, whereas cells in internal locations may receive signals on all sides from many different neighbors (Figure 1B). The choice of whether a cell is on the outside or inside of an embryo may largely be due to chance and so stochastic factors can be important as well. As explained below, cell position is known to be important in establishing different cell lineages in the early mammalian embryo.
In mammals, the first overt evidence for different cell lineages is apparent at very early stages of embryonic development. We consider this below when we describe the sequential stages of early development in mammals, from zygote to the implanted blastocyst. Figure 2 provides a road map of the major differentiation events in early mammalian development, and the changes from mammalian zygote to blastocyst are charted below.
Fig2. A road map for early differentiation events in human embryos. At, or shortly after, the late 8-cell stage, the embryo undergoes compaction and cell polarity develops (Box 4.2). Overt signs of resulting tissue differentiation first become apparent at the mammalian blastocyst stage, where there are two clearly different cell layers (as shown In Figure 4.4B). The outer trophoblast cells of the blastocyst (trophectoderm) give rise to cytotrophoblast that will form chorionic villi, and syncytiotrophoblast, which will ingress into uterine tissue. Tissues of the embryo will be formed exclusively by the epiblast cells of the inner cell mass that eventually give rise to three embryonic germ layers, ectoderm, endoderm, and mesoderm (see Figure 4.9 for their derivatives). Some embryonic epiblast cells are induced by extra-embryonic ectoderm to form primordial germ cells, the precursors of germ cells, that will later migrate to the gonads. Other cells in the inner cell mass, those of the hypoblast and also some from the epiblast, give rise to other extra-embryonic membranes. The dashed line indicates a possible dual origin of the extra-embryonic mesoderm. (Adapted from Gilbert SF [2006] Developmental Biology, 8th edn. Fig. 11.32, p. 352. By permission of Oxford University Press.)
