Human Developmental Biology. Danton Inc. O'Day
it. This is just one example of many intrinsic pathways.
Death Receptors and the Extrinsic Pathway
Alternatively, surface receptors can be activated by specific ligands that bind to “death receptors” (i.e., “Extrinsic Pathway”). Death receptors are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily. They make up a subfamily characterized by the intracellular death domain (DD). The extrinsic pathway is typically mediated by immune cells to initiate intracellular signaling and the downstream activation of relevant caspases. Some work suggests both intrinsic and extrinsic pathways mediate apoptosis during oogenesis and likely of aging eggs after fertilization.
The diagram presented in Figure 3.12 shows some of the signaling events that are initiated when tumor necrosis factor alpha (TNFα) leads to apoptosis. It should be noted that TNFα also mediates other signaling pathways involved in normal cellular functions. For TNF-mediated apoptosis the acronym TRAIL (tumor-necrosis factor-related apoptosis inducing ligand) is used to specify this function versus the factor’s other roles.
Figure 3.12. The signaling events initiated by TNFα binding.
The binding of TNFα to its receptor (TNF-receptor or TNFR) makes the receptor’s intracellular death domain available for binding to TRADD (TNFR-associated death domain). TRADD is an adaptor that in turn directs the binding of FADD (Fas-associated death domain), another adaptor that mediates the binding of pro-caspase-8 to this multiprotein complex. This leads to the proteolytic processing of the inactive pro-caspase-8 into the active caspase-8 enzyme. Caspase-8 is an initiator caspase that in turn proteolytically activates several other caspases. The activated caspases-3,6 and 7 are effector caspases that proteolytically digest a number of target proteins, ultimately leading to apoptosis. There are a number of other apoptosis-specific pathways, each of which involves unique sets of adaptor proteins and caspases and each of which is designed to direct apoptosis at a specific place or time in human development or other aspects of cell function.
Chapter 4
Egg Differentiation and Genetic Abnormalities
The egg is a differentiated cell type. It is specialized in many ways: to receive the sperm during fertilization, to supply the majority of the cytoplasm for early development, to provide half of the genome for the zygote and to provide information to initiate the events of early development. The egg specializes early and subsequently undergoes unequal cell divisions during meiosis (releasing smaller polar bodies) so that this differentiated egg cytoplasm is not greatly diminished. One aspect of egg structure is the presence of various "envelopes" that surround it. As we will see, these cellular and non-cellular (extracellular matrix) components are critical to the survival and fertilization of the egg.
The Egg is a Differentiated Cell
Compared to other cells in the body, the egg is a very large, essentially round cell. The growth and differentiation phases occur simultaneously during prophase I of meiosis. At this stage the nucleus is called a germinal vesicle. The germinal vesicle is a very specialized nucleus. For example it contains a minimal version of "lampbrush chromosomes", common to other species, that are actively involved in gene transcription. The egg itself is surrounded by egg coats which consists of cells (cumulus oophorus; corona radiata) and zona pellucida (protein “shell”) as will be detailed in Chapter 6 when we discuss its role in fertilization. The egg also contains many specialized organelles in its cytoplasm. Cortical granules (see Chapter 6) align adjacent to the egg cell membrane in anticipation of fertilization. Adjacent to the nucleus are the annulate lamellae. The annulate lamellae consist of parallel stacks of nuclear envelope-like membranes that lie adjacent to the nucleus which may give rise to them. Evidence indicates that the annulate lamellae are essential for the formation of the pronuclei during fertilization.
Many animals have large store of yolk but this is not the case in humans. The human egg has a minimal amount of yolk. Interestingly, yolk proteins made in liver and are transported to egg via the blood. Yolk proteins are taken into growing oocytes via receptor-mediated endocytosis. The small amount of yolk is due to the fact that the developing embryo only needs internal nutrients until implantation. At that time it obtains nutrients from the maternal body via the placental relationship.
Meiotic Divisions
Human gametes, like those of mammals and most other animals, are haploid (i.e., contain only half the amount of somatic DNA). This is because the diploid state will be re-established at fertilization when the haploid sperm and haploid egg fuse to produce the diploid zygote. The goal of meiosis is to reduce the diploid state to haploid via two meiotic divisions. The problem with meiosis during oogenesis is the egg has gone through a period of significant growth and differentiation. During normal meiosis, the cytoplasmic volume is also reduced. If this occurred in oogenesis, this would be a significant waste of energy since all the work that was done to make all the egg components would be reduced at each stage of meiosis. As a result, the egg has mechanism that reduces the genetic complement while not significantly reducing its cytoplasmic volume.
The nucleus of the egg is off-center, so that when meiotic cell divisions occur, the division of the egg is unequal. The eccentric nucleus leads to large secondary oocyte (meiosis I) or ovum (meiosis II) plus the release of much smaller polar bodies. Thus meiosis in total produces a single fertilizable egg plus 2 or 3 polar bodies (if the polar body itself divides) rather than the normal number of four meiotic cells. Little research has been done on the importance and fate of polar bodies. The consensus is polar bodies do not play a role in fertilization and may be reabsorbed by the egg or embryo or simply die off.
Figure 4.1. A fertilized egg showing two polar bodies (false colored blue) and the fusing pronuclei (false colored green).
As shown in Figure 4.1., the fusing haploid pronuclei (false coloured green in right panel) are seen in the centre of the egg while the two released pronuclei (false coloured blue in right panel) that resulted from the meiotic divisions are situated outside the egg. Sometimes a third polar body is observed which is due to the division of the first polar body. To reiterate, the polar bodies have no known developmental function other than to reduce the genetic complement of the egg without causing a large reduction in the egg cytoplasm. The zona pellucida (dark wide circular material outside the egg) surrounds the egg and polar bodies.
Meiosis and Genetic Abnormalities: Non-Disjunction
Non-Disjunction: With non-disjunction, the meiotic chromosomes don’t pull apart. As a result one cell gets both sister chromatids (that each will become a chromosome) while the other cell doesn't get that chromosome. Non-disjunction can occur during either meiosis I or meiosis II as illustrated in the following graphic (Figure 4.2). This figure summarizes how gametes can end up with one more or one less chromosome when non-disjunction occurs during meiosis.
Figure 4.2. Non-disjunction during meiosis leads to abnormal chromosome numbers in developing eggs.
The following points summarize the issue of non-disjunction:
•Non-disjunction leads to abnormal chromosome numbers in eggs.
•If one daughter gamete has an extra chromosome (i.e., 24 rather than the normal 23) the resulting syndrome is called trisomy (3 copies of the same chromosome will exist after fertilization) e.g., Down Syndrome—trisomy 21 is due to an extra copy of chromosome 21.
•If the daughter gamete has 1 less chromosome (i.e., a total of 22 rather than the normal 23) it results in monosomy (e.g., Turner Syndrome—lacks a sex chromosome). Most cases