Cellular Mechanisms of Development PDF

Automatic ZoomActual SizePage Width100%50%75%100%125%150%200%300%400% Chapter 10: Pregnancy, Development, and Aging 348 Lesson 10.3 **Cellular Mechanisms of Development** Introduction Mammalian development begins with the zygote, a single cell that gives rise to all tissue types and organs in...

Automatic ZoomActual SizePage Width100%50%75%100%125%150%200%300%400% Chapter 10: Pregnancy, Development, and Aging 348 Lesson 10.3 **Cellular Mechanisms of Development** Introduction Mammalian development begins with the zygote, a single cell that gives rise to all tissue types and organs in the mature organism. The organization and transformation of cells during the developmental period are carried out by a complex array of cellular mechanisms that depend on the precise coordination of signal and response (ie, development is highly regulated in both space and time). This lesson provides an overview of some of the cellular and molecular mechanisms that can be used to execute a developmental plan. Mechanisms such as asymmetrical cell division, cell signaling and migration, differential gene expression, and programmed cell death act synergistically to drive the proper patterning and growth of the embryo. 10.3.01 Cell Potency and Specialization A single-celled zygote has the potential to give rise to every cell type (ie, both embryonic and extraembryonic) and is thus considered **totipotent** (Figure 10.10). Because of asymmetrical cell division during embryonic cleavage, the fate of specific embryonic blastomeres becomes progressively restricted beyond the 8-cell stage. As an embryo progresses toward blastulation, individual blastomeres are restricted to either embryonic or extraembryonic cell types; therefore, the blastomeres are no longer totipotent. Instead, these cells are considered **pluripotent** (ie, able to give rise to either embryonic or extraembryonic cell types but not both). For example, as the embryo approaches the blastocyst stage, trophoblast cells are already restricted to extraembryonic cell fates (eg, precursors to the placenta) and are no longer able to contribute to the embryo itself (Figure 10.10). As development continues, the fate of individual embryonic cells becomes even more restricted. At neural tube closure, the cells of the neural tube are **multipotent**, or able to generate multiple cell types within a restricted population or lineage (eg, ectodermal cells are restricted to neural, epidermal, and neural crest cell fates). Continued development may yield further restriction of multipotent cells or **unipotent** cells (ie, generate only one cell type). Through [differential gene expression](javascript:void(0)), **terminal differentiation** of these cells leads to unique cell types with characteristic biochemical signatures, structures, and functions. Chapter 10: Pregnancy, Development, and Aging 349 **Figure 10.10** Cell potency. **Stem cells** retain their potency and ability to divide but may generate daughter cells that terminally differentiate into specific cell types. Depending on the source, stem cells can give rise to many cell types (eg, pluripotent embryonic stem cells of the inner cell mass) or only a few (eg, multipotent [hematopoietic](javascript:void(0)) [stem cells](javascript:void(0))). Although stem cells are usually discussed in the context of embryonic development, it is important to note that stem cell populations also exist in many adult tissues (eg, bone marrow, brain). Some stem cell populations can **self-renew**. As a result of asymmetrical cell division, one daughter cell may terminally differentiate into a specific cell type, whereas the other retains stem cell properties that maintain the progenitor cell pool (Figure 10.11). For example, during early spermatogenesis, unipotent spermatogonial stem cells generate daughter cells that either differentiate into primary spermatocytes or maintain the spermatogonial stem cell population so that additional spermatozoa can be generated continually throughout life (see Concept 9.2.02). A diagram of a cell Description automatically generated Chapter 10: Pregnancy, Development, and Aging 350 If stem cell division is symmetrical, both daughter cells may retain stem cell properties in some instances, thereby enlarging the stem cell population. In other instances, both daughter cells derived from the stem cell may terminally differentiate, effectively depleting the stem cell population over time (Figure 10.11). **Figure 10.11** Stem cell division and self-renewal. The process by which cells become committed to a specific cell fate occurs in stages. Totipotent cells are said to be unspecified. **Cell specification** begins very early in development when a cell becomes capable of differentiating into a particular cell type on its own in a neutral environment. However, the fate of a specified cell is not fixed and may be changed by external cues. For example, a cell specified as mesodermal may retain the potential to become a neuron if placed in conditions which induce neuronal development. A cell is said to be **determined** when it is tied to a specific fate, even when placed in an alternate environment (ie, the cell\'s developmental fate is *not* altered by external cues). For example, once a mesodermal cell is determined as a muscle cell precursor, that mesodermal cell cannot become a neuron, even when placed in conditions which induce neuronal development. Once determined, progenitor cells are induced to undergo terminal differentiation, developing specialized structures and functions. In some cases (eg, neuronal progenitor cells), terminally differentiating cells may leave the [cell cycle](javascript:void(0)) and do not divide again. 10.3.02 Gene Regulation in Development A fundamental question in development centers on how differences arise in seemingly equivalent (ie, totipotent) embryonic cells. Although the full mechanism is unknown, the progressive determination and differentiation of unique cell types are directed by differential gene expression resulting from a combination of cell **intrinsic** (internal) and **extrinsic** (external) **factors**. Early embryogenesis is driven largely by intrinsic factors, with later patterning involving extrinsic factors, resulting in progressive cell fate restriction, as summarized in Table 10.2.  Chapter 10: Pregnancy, Development, and Aging 351 **Table 10.2** Cell intrinsic and extrinsic factors in early embryogenesis. In the early cleavage stage of embryogenesis, cell division is rapid and the embryo is dependent on oocyte stores of mRNA and proteins. The embryonic genome becomes active beginning at the 4- to 8-cell stage, but oocyte contributions persist through the blastocyst stage. The embryonic genome must undergo extensive epigenetic remodeling before genome activation. This remodeling allows [transcription](javascript:void(0)) [factors](javascript:void(0)) better access to [chromatin](javascript:void(0)), which is necessary for the proper regulation of embryonic gene expression. During remodeling, [cytosine nucleotides](javascript:void(0)) may be [methylated](javascript:void(0)), which generally has a silencing effect on gene expression. Most genomic DNA is demethylated shortly after fertilization; however, for certain genes, the maternal and paternal methylation patterns remain intact, and alleles are not functionally equivalent. Therefore, methyl group retention on specific alleles leads to parent-specific gene expression in offspring, a phenomenon known as **genomic imprinting** (Figure 10.12). When the paternal allele is imprinted (ie, methylated), gene expression occurs only from the maternal allele and vice versa. A chart of a cell extrinsic factor Description automatically generated Chapter 10: Pregnancy, Development, and Aging 352 **Figure 10.12** Genomic imprinting. Because of differences in primary sex determination, individuals with two X chromosomes have twice as many copies of X chromosome genes than XY individuals. This phenomenon has important implications in terms of X-linked inheritance (discussed in Concept 7.3.02). XX individuals compensate for this disparity via **X chromosome inactivation** (**X inactivation**) in early embryonic development. During X inactivation, one X chromosome in each cell becomes inactivated due to expression of the *XIST* (X-inactive specific transcript) gene. *XIST* expression initiates epigenetic X chromosome modification, resulting in extensive chromatin remodeling, DNA methylation, and gene silencing (see Concept 2.4.02). This causes the X chromosome expressing *XIST* to condense, forming a compact structure known as a **Barr body**. X chromosome inactivation occurs in each embryonic cell on a random basis. Therefore, in any given cell from an XX individual, the active X chromosome may be of paternal or maternal origin. If an XX individual is [heterozygous](javascript:void(0)) for an [X-linked](javascript:void(0)) trait, roughly half of the individual\'s cells express the maternal allele, and the other half express the paternal allele (Figure 10.13).  Chapter 10: Pregnancy, Development, and Aging 353 **Figure 10.13** X chromosome inactivation. As discussed in Concept 2.4.03, regulatory elements found outside of DNA coding regions contain enhancer sequences that, when bound by transcription factors, modulate gene expression levels. Tissue-specific gene expression during development arises due to unique combinations of transcription factors expressed in individual cells. Enhancer sequences are often modular, meaning that distinct enhancers associated with a single gene can regulate that gene\'s expression in different tissues and at different times during development. Only specific combinations of transcription factors bound to an enhancer allow a gene to be expressed in a particular cell type. This same gene remains unexpressed in cells that do not have the correct combination of transcription factors. For example, the transcription factor PTF1A is known to be expressed in both pancreatic and cerebellar progenitor cells during development (Figure 10.14). Two distinct regulatory enhancers controlling *PTF1A* expression exist: one that controls expression in the developing cerebellum and one that controls expression in the developing pancreas. Mutations within individual enhancers disrupt development in a tissue-specific fashion, affecting either the pancreas or cerebellum but not both (ie, a mutation in the pancreatic enhancer affects the pancreas, but not the cerebellum). Diagram of a cell with different types of cells Description automatically generated Chapter 10: Pregnancy, Development, and Aging 354 **Fig 10.14** Example of enhancer sequence modularity. In addition to an organism\'s genetic makeup, environmental conditions also play a role in development. Environmental cues may influence organism development by altering cell signaling and gene expression at crucial times during development. Epigenetic changes due to diet, temperature, and other environmental exposures may alter the progression of development in both small and highly impactful ways. One well-known example of environmental effects during human development involves deficiencies in dietary folate. Low maternal folate intake can affect neural tube closure in the developing embryo and is one of the leading causes of neural tube defects in humans. Although the exact mechanism is unknown, it is hypothesized that disruption of folic acid metabolism may affect DNA methylation in the developing nervous system. It is estimated that 25%-30% of neural tube defects in humans can be prevented by taking supplemental folate during pregnancy. 10.3.03 Cell Signaling and Migration Cell-cell signaling drives many developmental cellular activities (eg, division, adhesion, migration, differentiation). For example, ectodermal cells are induced to become neural plate cells in response to signal secretion by the underlying notochord (see Concept 10.2.02). **Induction** involves the cells or tissues that produce signaling molecules (ie, **inducers**) and the responding cells or tissues, which must be **competent** (ie, able to receive and respond to inductive signals). For example, a secreting cell induces differentiation only in neighboring cells that express the correct receptors and signal transduction machinery. Often, inductive interactions are reciprocal: The inducing cells trigger the secretion of new inductive signals in the neighboring cells, which then act on the original inducing cells to further refine developmental fates. For example, in [vertebrate eye](javascript:void(0)) development, the ectoderm overlying the optic vesicle (ie, developing eye) induces lens formation, and the newly formed lens cells reciprocate, instructing the optic vesicle to form the retina. Inducers are most often paracrine factors but may also be autocrine or juxtacrine signals (Figure 10.15). Secreted **paracrine** signals exert their effects on nearby cells via diffusion, whereas **autocrine** signals exert effects on the same cell from which they are secreted. **Juxtacrine** signals are cell surface ligands from one cell that interact with receptors on adjacent cells. Before circulatory system development, endocrine signaling is not prominent.  Chapter 10: Pregnancy, Development, and Aging 355 **Figure 10.15** Types of inductive cell signaling. Signaling gradients are a key feature of early embryonic development. **Morphogens** are inductive paracrine factors that diffuse from a signaling cell to form a concentration gradient within nearby tissues. The fates of receiving (ie, competent) cells within a diffusible distance of the morphogen are influenced by the concentration of morphogen to which the receiving cells are exposed (Figure 10.16). In addition to diffusion, morphogen gradients are influenced by time-dependent morphogen destruction and/or uptake into cells. Overlapping morphogen gradients may be used to establish precise patterns of gene expression and cell differentiation during development. **Figure 10.16** Morphogens influence the fates of competent cells based on morphogen concentration. A diagram of a cell Description automatically generated  Chapter 10: Pregnancy, Development, and Aging 356 For example, morphogen concentration in the neural tube influences the differentiation of spinal neuron populations along the dorsal-ventral axis of the neural tube. Opposing concentrations of the morphogens bone morphogenetic protein (BMP), Wnt, and sonic hedgehog (Shh) in the neural tube specify dorsal and ventral cell fates (Figure 10.17). High levels of BMP and Wnt are secreted from the overlying ectoderm and most dorsal regions of the neural tube, inducing gene expression that leads to dorsal cell fates (ie, differentiation into [sensory](javascript:void(0)) [neurons](javascript:void(0))). In contrast, high levels of Shh secretion from the notochord and most ventral regions of the neural tube induce the expression of genes that lead to ventral cell fates (ie, differentiation into motor neurons). **Figure 10.17** Opposing morphogen gradients in neural tube development. Although less common than paracrine signaling, some juxtacrine signaling pathways are crucial in developmental biology. For example, the Notch pathway involves a Notch receptor protein embedded in an inducing cell membrane that interacts with a ligand (eg, Delta) embedded in the receiving cell membrane. Adjacent progenitor cells may often express both the Notch receptor and its ligand. This type of signaling may be used to induce the differentiation of one progenitor cell while keeping the other in an undifferentiated state, a process known as **lateral inhibition**. For example, in two adjacent cells, the cell in which the Notch pathway is first engaged leads to the inhibition of the Delta ligand within the same cell, thereby preventing the ligand from activating Notch in the adjacent cell. Therefore, the first cell to activate the Notch pathway undergoes differentiation, and the adjacent cell remains undifferentiated, as shown in Figure 10.18. A diagram of a brain Description automatically generated Chapter 10: Pregnancy, Development, and Aging 357 **Figure 10.18** Notch signaling and lateral inhibition. As development proceeds, some cells must migrate short and long distances to arrive at the appropriate locations. For example, during gastrulation, many complex cell movements and rearrangements occur to transform the embryo from a flat, two-layered disk into a complex tubular structure. Cells migrate by responding to environmental cues and surrounding cells. Because of embryonic patterning, a migrating cell encounters different environments as it moves within the embryo. Cells migrate (either individually or in groups) in response to short- and long-range signals to reach their final destination. The migration of neural crest cells is an example of cell migration during development (see Concept 10.2.02). Following neural tube closure, some cells (ie, neural crest cells) lose their adhesive junctions and separate from the epithelium in a process called **delamination**. Once delaminated, neural crest cells migrate extensively along the anterior-posterior axis, giving rise to a wide variety of different cell types, including cells of the peripheral nervous system, adrenal medulla, melanocytes, and head/neck connective tissues. Both external (eg, environmental signals) and internal factors (eg, changing patterns of adhesion proteins) drive neural crest migration. These factors guide cells via both attractive and repulsive interactions through different environments and over long distances. 10.3.04 Programmed Cell Death Just as cell proliferation is crucial during embryonic development and morphogenesis, so too is restricting the number of cells produced. Normal development often generates an excess number of cells, with surplus cells later removed via [apoptosis](javascript:void(0)) (ie, programmed cell death). During mammalian development, apoptosis occurs at several points, including during blastocyst formation, shaping of tubular structures, and separation of digits (Figure 10.19). Chapter 10: Pregnancy, Development, and Aging Correctly timed apoptosis is critical during vertebrate limb development. During development, each digit is specified by exposure to sequential signaling gradients (eg, morphogens) from the posterior interdigital tissue (ie, mesodermal tissue between each digit). After digit formation, apoptosis of the interdigital webbing is induced to separate the limb bud into distinct digits.