Developmental biology has its own set of core concepts and terminology that may be confusing or foreign to the student of genetics. We therefore provide a brief summary of a number of key concepts and terms used in this chapter.

Cellular Processes During Development

During development, cells divide (proliferate), acquire novel functions or structures (differentiate), move within the embryo (migrate), and undergo programmed cell death (often through apoptosis). These four basic cellular processes act in various combinations and in different ways to allow growth and morphogenesis (literally, the “creation of form”), thereby creating an embryo of normal size and shape, containing organs of the appropriate size, shape, and location, and consisting of tissues and cells with the correct architecture, structure, and function.

Although growth may seem too obvious to discuss, growth itself is carefully regulated in mammalian development, and unregulated growth is disastrous. The mere doubling (one extra round of cell division) of cell number (hyperplasia) or an increase of cell size (hyper trophy) in an organism can be fatal. Dysregulation of growth of segments of the body can cause severe deformity and dysfunction, such as in hemihyperplasia and other segmental overgrowth disorders. Furthermore, the exquisite differential regulation of growth can change the shape of a tissue or an organ.

Morphogenesis is accomplished in the developing organism by the coordinated interplay of the mechanisms introduced in this section. In some contexts, morphogenesis is used as a general term to describe all of development, but this is formally incorrect because morphogenesis has to be coupled to the process of growth discussed here to generate a normally shaped and functioning tissue or organ.

Human Embryogenesis

This description of human development begins where Chapter 2 ends, with fertilization. After fertilization, the embryo undergoes a series of cell divisions without overall growth, termed cleavage. The single fertilized egg undergoes four divisions to yield the 16-cell morula by day 4 (Fig. 1). At day 5, the embryo transitions to become a blastocyst, in which cells that give rise to the placenta form a wall, inside of which the cells that will make the embryo itself aggregate to one side into what is referred to as the inner cell mass. This is the point at which the embryo acquires its first obvious manifestation of polarity, an axis of asymmetry that divides the inner cell mass (most of which goes on to form the mature organism) from the embryonic tissues that will go on to form the chorion, an extraembryonic tis sue (e.g., placenta) (Fig. 2). The inner cell mass then separates again into the epiblast, which will make the embryo proper, and the hypoblast, which will form the amniotic membrane.

Fig1. Human development begins with cleavage of the fertilized egg. (A) The fertilized egg at day 0 with two pronuclei and the polar bodies. (B) A two-cell embryo at day 1 after fertilization. (C) A four-cell embryo at day 2. (D) The eight-cell embryo at day 3. (E) The 16-cell stage later in day 3, followed by the phenomenon of compaction, whereby the embryo is now termed a morula (F, day 4). (G) The formation of the blastocyst at day 5, with the inner cell mass indicated by the arrow. Finally, the embryo (arrow) hatches from the zona pellucida (H). (Reprinted with permission from Jones KL: Smith’s recognizable patterns of human malformation, ed 6, Philadelphia, 2005, WB Saunders.)

Fig2. Cell lineage and fate during preimplantation development. Embryonic age is given in time after fertilization in humans: (A) 6 days, (B) 7 days, (C) 8 days postfertilization. (Reprinted with permission from Moore KL, Persaud TVN: The developing human: clinically oriented embryology, ed 6, Philadelphia, 1998, WB Saunders.)

The embryo implants in the endometrial wall of the uterus in the interval between days 7 and 12 after fertilization. After implantation, gastrulation occurs, in which cells rearrange themselves into a structure consisting of three cellular compartments, termed the germ layers, comprising the ectoderm, mesoderm, and endoderm. The three germ layers give rise to different structures. The endodermal lineage forms the central visceral core of the organism. This includes the cells lining the main gut cavity, the airways of the respiratory system, and other similar structures. The mesodermal lineage gives rise to kidneys, heart, vasculature, and structural or supportive functions in the organism. Bone and muscle are nearly exclusively mesodermal and have the two main functions of structure (physical support) and providing physical and nutritive support of the hematopoietic system. The ectoderm gives rise to the central and peripheral nervous systems and the skin. During the complicated movements that occur in gastrulation, the embryo also establishes the major axes of the final body plan: anterior-posterior (cranial-caudal), dorsal-ventral (back-front), and left right axes, which are discussed later.

The next major stages of development involve the initiation of the nervous system, establishment of the basic body plan, and then organogenesis, which occupies weeks 4 to 8. The position and basic structures of all the organs are now established, and the cellular components necessary for their full development are now in place. It is during this phase of embryonic development that neural tube defects occur, as we explore next.

Neural Tube Defects

Neural tube defects (NTDs) are among the most common and devastating birth defects. Anencephaly and spina bifida are NTDs that frequently occur together in families and are considered to have a common pathogenesis. In anencephaly, the forebrain, overlying meninges, vault of the skull, and skin are all absent. Many infants with anencephaly are stillborn, and those born alive survive a few hours at most. Approximately two-thirds of affected infants are female. In spina bifida, there is failure of fusion of the arches of the vertebrae, typically in the lumbar region. There are varying degrees of severity, ranging from spina bifida occulta, in which the defect is in the bony arch only, to spina bifida aperta, in which a bone defect is also associated with meningocele (protrusion of meninges) or meningomyelocele (protrusion of neural elements as well as meninges through the defect).

A small proportion of NTDs have known specific causes, for example, amniotic bands, some single-gene defects with pleiotropic expression, some chromosomal disorders, and some teratogens. Most NTDs, however, are isolated defects of unknown cause.

Maternal Folic Acid Deficiency and Neural Tube Defects. NTDs were long believed to follow a multi factorial inheritance pattern determined by multiple genetic and environmental factors, as introduced generally in Chapter 9. It was therefore a stunning discovery to find that the single greatest factor in causing NTDs is a vitamin deficiency. The risk for NTDs was found to be inversely correlated with maternal serum folic acid levels during pregnancy, with a threshold of 200 µg/L, below which the risk for NTD becomes significant. Along with reduced blood folate levels, elevated homo cysteine levels were also seen in the mothers of children with NTDs, suggesting that a biochemical abnormality was present at the step of recycling of tetrahydrofolate to methylate homocysteine to methionine. Folic acid levels are strongly influenced by dietary intake and can become depressed during pregnancy even with a typical intake of ~230 µg/day. The impact of folic acid deficiency is exacerbated by a genetic variant of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), caused by a common missense variant that makes the enzyme less stable than normal. Instability of this enzyme hinders the recycling of tetrahydrofolate and interferes with the methylation of homocysteine to methionine.

The variant allele is so common in many populations that between 5% and 15% of the population is homozygous for the variant. In studies of infants with NTDs and their mothers, it was found that mothers of infants with NTDs were twice as likely as controls to be homozygous for the allele encoding the unstable enzyme. How this enzyme defect contributes to NTDs and whether the abnormality is a direct result of elevated homocysteine levels, depressed methionine levels, or some other metabolic derangement remains undefined.

Prevention of Neural Tube Defects. There are two approaches to preventing NTDs. The first is to educate women to supplement their diets with folic acid 1 month before conception and continuing for 2 months after conception during the period when the neural tube forms. Dietary supplementation with 400 to 800 µg of folic acid per day for women who plan their pregnancies has been shown to reduce the incidence of NTDs by more than 75%. Since 1998, the United States has required cereal products labeled as enriched to be supplemented with 140 μg folic acid per 100 g flour as a public health measure to avoid the problem of women failing to supplement their diets individually during pregnancy. The Centers for Disease Control and Prevention estimates that this has reduced the number of infants born with NTDs by 1300 per year.

The second approach is to apply prenatal screening for all pregnancies and offer prenatal diagnosis to high risk pregnancies. Prenatal diagnosis of anencephaly and most cases of open spina bifida relies on detecting excessive levels of α-fetoprotein (AFP) and other fetal sub stances in the amniotic fluid and by ultrasonographic scanning, as we shall discuss further in Chapter 18. However, less than 5% of all patients with NTDs are born to women with previous affected children. For this reason, screening of all pregnant women for NTDs by measurements of AFP and other fetal substances in maternal serum is now widespread. Thus we anticipated that a combination of preventive folic acid therapy and maternal AFP screening would provide major public health benefits by drastically reducing the incidence of NTDs, which it has by 35% compared with presupple mentation levels.

Human Fetal Development

The embryonic phase of development occupies the first 2 months of pregnancy and is followed by the fetal phase of development, which is concerned primarily with the maturation and further differentiation of the components of the organs. For some organ systems, development does not cease at birth. For example, the brain undergoes substantial postnatal development, and limbs undergo epiphyseal growth and ultimately closure after puberty.

The Germ Cell: Transmitting Genetic Information

In addition to growth and differentiation of somatic tis sues, the organism must also specify which cells will go on to become the gametes of the mature adult. The germ cell compartment serves this purpose. As described in Chapter 2, cells in the germ cell compartment become committed to undergoing gametogenesis and meiosis in order that the species can pass on its genetic complement and facilitate the recombination and random assortment of chromosomes. In addition, the sex specific epigenetic imprint that certain genes require must be reset within the germ cell compartment.

The Stem Cell: Maintaining Regenerative Capacity in Tissues

 In addition to specifying the program of differentiation that is necessary for development, the organism must also set aside tissue-specific stem cells that can regenerate differentiated cells during adult life. The best-characterized example of these cells is in the hematopoietic system. Among the 1011 to 1012 nucleated hematopoietic cells in the adult organism are ~104 to 105 cells that have the potential to generate any of the more specialized blood cells on a continuous basis during a lifetime. Hematopoietic stem cells can be transplanted to other humans and completely reconstitute the hematopoietic system. A system of interacting gene products maintains a properly sized pool of hematopoietic stem cells. These regulators permit a balance between the maintenance of stem cells through self- replication and the generation of committed precursor cells that can go on to develop into the various mature cells of the hematopoietic system (Fig. 3).

Fig3. The development of blood cells is a continuous process that generates a full complement of cells from a single, totipotent hematopoietic stem cell. This hematopoietic stem cell is a committed stem cell that differentiated from a more primitive mesodermal stem cell. RBC, Red blood cell. (Reprinted with permission from Stamatoyannopoulos G, Nienhuis AW, Majerus PW, et al: The molecular basis of blood diseases, ed 2, Philadelphia, 1994, WB Saunders.)

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المزيد

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مواضيع ذات صلة

Human Gametogenesis and Fertilization

Ovulation

CELL SIGNALING

المواعيد السريرية والجنينية Clinical and embryological timings

طبيعة مواد التكاثر اللاجنسي

التكاثر اللاجنسي

المفاهيم الأساسية في علم الجنين

مقدمة في علم الجنين