FUHSO Embryonic Induction, Determination & Differentiation PDF

EMBRYONIC INDUCTION, DETERMINATION AND DIFFERENTIATION LECTURER’S NAME: Prof. AKINLOLU, Abdulazeez Adelaja Department of Anatomy, FUHSO Date: 28th April, 2023. Time: 10am – 11am OUTLINE...

EMBRYONIC INDUCTION, DETERMINATION AND DIFFERENTIATION LECTURER’S NAME: Prof. AKINLOLU, Abdulazeez Adelaja Department of Anatomy, FUHSO Date: 28th April, 2023. Time: 10am – 11am OUTLINE 1. Introduction 2. Phases of human development: Growth, Morphogenesis and Differentiation 3. Embryonic Induction 4. Developmental signaling between Interactants 5. Developmental signaling pathways 6. Signaling pathways of embryogenesis 7. Class Assignment Phases of Development Human development may be divided into interrelated three phases: The first phase is growth, which involves cell division and the elaboration of cell products. The second phase is morphogenesis (development of shape, size, or other features of a particular organ or part or the whole of the body). Morphogenesis is an elaborate process during which many complex interactions occur in an orderly sequence. The movement of cells allows them to interact with each other during the formation of tissues and organs. The third phase is differentiation (maturation of physiologic processes). Completion of differentiation results in the formation of tissues and organs that are capable of performing specialized functions. Development results from genetic plans in the chromosomes. Most developmental processes depend on a precisely coordinated interaction of genetic and environmental factors. Several control mechanisms guide differentiation and ensure synchronized development, such as tissue interactions, regulated migration of cells and cell colonies, controlled proliferation, and programmed cell death. Each system of the body has its own developmental pattern. Embryonic development is essentially a process of growth and increasing complexity of structure and function. Growth is achieved by mitosis together with the production of extracellular matrices, whereas complexity is achieved through morphogenesis and differentiation. The cells that make up the tissues of very early embryos are pluripotential, which under different circumstances are able to follow more than one pathway of development. This broad developmental potential becomes progressively restricted as tissues acquire the specialized features necessary for increasing their sophistication of structure and function. Such restriction presumes that choices must be made to achieve tissue diversification. At present, most evidence indicates that these choices are determined, not as a consequence of cell lineage, but rather in response to cues from the immediate surroundings, including the adjacent tissues. As a result, the architectural precision and coordination that are often required for the normal function of an organ appear to be achieved by the interaction of its constituent parts during development. Embryonic Induction The interaction of tissues during development is a recurring theme in embryology. The interactions that lead to a change in the course of development of at least one of the interactants are called inductions. Numerous examples of such inductive interactions can be found in the literature; for example, during development of the eye, the optic vesicle induces the development of the lens from the surface ectoderm of the head. When the optic vesicle is absent, the eye fails to develop. Moreover, if the optic vesicle is removed and placed in association with surface ectoderm that is not usually involved in eye development, lens formation can be induced. Clearly then, development of a lens is dependent on the ectoderm acquiring an association with a second tissue. In the presence of the neuroectoderm of the optic vesicle, the surface ectoderm of the head adopts a pathway of development that it would not otherwise have taken. In a similar fashion, many of the morphogenetic tissue movements that play such important roles in shaping the embryo also provide for the changing tissue associations that are fundamental to inductive tissue interactions. Schematic transverse section through the head of an embryo in the region of the developing eyes to illustrate inductive tissue interaction. At the normal site (lower right), observe that the optic stalk, the precursor of the optic cup, has acted on the surface ectoderm of the head to induce formation of a lens vesicle, the primordium of the lens. On the opposite side, the optic stalk was cut and the optic vesicle removed. As a result, no lens placode (first indication of a lens) developed. At the abnormal site (upper right), the optic vesicle removed from the right side was inserted deep to the skin. Here, it acted on the surface ectoderm to induce the formation of a lens vesicle that has induced the formation of an optic cup (primordium of eyeball). Developmental Signaling between Interactants The fact that one tissue can influence the developmental pathway adopted by another tissue presumes that a signal passes between the two interactants. Analysis of the molecular defects in mutant strains that show abnormal tissue interactions during embryonic development, and studies of the development of embryos with targeted gene mutations have begun to reveal the molecular mechanisms of induction. The mechanism of signal transfer appears to vary with the specific tissues involved. In some cases, the signal appears to take the form of a diffusible molecule, such as sonic hedgehog, that passes from the inductor to the reacting tissue. In others, the message appears to be mediated through a nondiffusible extracellular matrix that is secreted by the inductor and with which the reacting tissue comes into contact. In still other cases, the signal appears to require that physical contacts occur between the inducing and responding tissues. Regardless of the mechanism of intercellular transfer involved, the signal is translated into an intracellular message that influences the genetic activity of the responding cells. Laboratory studies have established that the signal can be relatively nonspecific in some interactions. Under experimental conditions, the role of the natural inductor in a variety of interactions has been shown to be mimicked by a number of heterologous tissue sources and, in some instances, even by a variety of cell-free preparations. These studies suggest that the specificity of a given induction is a property of the reacting tissue rather than that of the inductor. Inductions should not be thought of as isolated phenomena. Often they occur in a sequential fashion that results in the orderly development of a complex structure; for example, following induction of the lens by the optic vesicle, the lens induces the development of the cornea from the surface ectoderm and adjacent mesenchyme. This ensures the formation of component parts that are appropriate in size and relationship for the function of the organ. In other systems, there is evidence that the interactions between tissues are reciprocal. During development of the kidney, for instance, the metanephric diverticulum (ureteric bud) induces the formation of tubules in the metanephric mesoderm. This mesoderm, in turn, induces branching of the diverticulum that results in the development of the collecting tubules and calices of the kidney. To be competent to respond to an inducing stimulus, the cells of the reacting system must express the appropriate receptor for the specific inducing signal molecule, the components of the particular intracellular signal transduction pathway, and the transcription factors that will mediate the particular response. Experimental evidence suggests that the acquisition of competence by the responding tissue is often dependent on its previous interactions with other tissues. For example, the lens-forming response of head ectoderm to the stimulus provided by the optic vesicle appears to be dependent on a previous association of the head ectoderm with the anterior neural plate. The ability of the reacting system to respond to an inducing stimulus is not unlimited. Most inducible tissues appear to pass through a transient, but more or less sharply delimited physiologic state in which they are competent to respond to an inductive signal from the neighboring tissue. Because this state of receptiveness is limited in time, a delay in the development of one or more components in an interacting system may lead to failure of an inductive interaction. Regardless of the signal mechanism employed, inductive systems seem to have the common feature of close proximity between the interacting tissues. Experimental evidence has demonstrated that interactions may fail if the interactants are too widely separated. Consequently, inductive processes appear to be limited in space as well as by time. Because tissue induction plays such a fundamental role in ensuring the orderly formation of precise structure, failed interactions can be expected to have drastic developmental consequences (e.g., congenital anomalies such as absence of the lens). Sketches of three possible methods of transmission of signal substances in inductive cell interactions. A, Diffusion of signal substances. The signal appears to take the form of a diffusible molecule that passes from the inductor to the reacting tissue. B, Matrix-mediated interaction. The signal is mediated through a nondiffusible extracellular matrix, secreted by the inductor, with which the reacting tissue comes in contact. C, Cell contact-mediated interaction. The signal requires physical contact between the inducing and responding tissues. (Modified from Grobstein C: Adv Cancer Res 4:187, 1956; and Saxen L: In Tarin D [ed]: Tissue Interactions in Carcinogenesis. London, Academic Press, 1972.) Developmental Signaling Pathways Normal embryogenesis is regulated by several complex signaling cascades. Mutations or alterations in any of these signaling pathways can lead to birth defects. Many signaling pathways are cell autonomous and only alter the differentiation of that particular cell, as seen in proteins produced by HOX A and HOX D gene clusters (in which mutations lead to a variety of limb defects). The first two limb malformations shown to be caused by mutations in the human HOX genes were synpolydactyly and hand-foot-genital syndrome, which result from mutations in HOXD13 and HOXA13, respectively. Synpolydactyly (SPD), or syndactyly type II, is defined as a connection between the middle and ring fingers and fourth and fifth toes, variably associated with postaxial polydactyly in the same digits. Synpolydactyly: (a) Two parents with the two affected boys to demonstrate the clinodactyly of the little finger in the parents. (b) The four affected children. The two boys are at 8 and 10 o’clock positions whereas the two girls are at 2 and 4 o’clock positions. (c–e) X-rays of hands and clinical/radiological appearance of the feet of the boy at 8 o’clock position. (f–h) X-rays of the hands and clinical/radiological appearance of the feet of the boy at 10 o’clock position. (i and j) X-rays of the hands of the girl at 2 o’clock position. (k and l) X-rays of the hands of the girl at 4 o’clock position. People with hand-foot-genital syndrome have abnormally short thumbs and first (big) toes, small fifth fingers that curve inward (clinodactyly), short feet, and fusion or delayed hardening of bones in the wrists and ankles. The other bones in the arms and legs are normal. Hand-foot-genital syndrome: Limb abnormalities. Photographs at age 1 month of left hand (A), showing extremely small thumb; and right foot (B), showing absence of hallux. Radiographs at age 5 years of both hands (C), showing extremely short first metacarpals, small pointed first distal phalanges, marked hypoplasia of all middle phalanges, especially the second and fifth, pseudoepiphyses of the third and fourth middle phalanges and the first and second metacarpals, and delayed ossification of the carpal centers; and both feet (D), showing absence of first digits apart from rudimentary bases of the first metatarsals, hypoplasia/absence of all middle phalanges, lack of epiphyses associated with the middle and distal phalanges, and abnormal tarsals with absent or fused cuneiforms. Other transcriptional factors act by influencing the pattern of gene expression of other adjacent cells. These short-range signal controls can act as simple on-off switches (paracrine signals); others, termed morphogens, elicit many responses depending on their level of expression with other cells. For example, Sonic hedgehog (Shh) is expressed in the notochord, the floorplate of the neural tube, the brain, and other regions such as the zone of polarizing activity of the developing limbs, and the gut. Sporadic and inherited mutations in the human Shh gene leads to holoprosencephaly - a midline defect of variable severity involving abnormal central nervous system (CNS) septation, facial clefting, single central incisor, hypotelorism, or a single cyclopic eye. Signaling Pathways of Embryogenesis Morphogens: These are diffusible molecules that specify which cell type will be generated at a specific anatomic location and direct the migration of cells and their processes to their final destination. These include retinoic acid, transforming growth factor β (TGF-β)/bone morphogenetic proteins (BMPs), and the hedgehog and the Wnt protein families. Notch/Delta: This pathway often specifies which cell fate precursor cells will adopt. Transcription factors: This set of evolutionarily conserved proteins activates or represses downstream genes that are essential for many different cellular processes. Many transcription factors are members of the homeobox or helix-loop-helix (HLH) families. Their activity can be regulated by all of the other pathways. Receptor tyrosine kinases (RTKs): Many growth factors signal by binding to and activating membrane-bound RTKs. These kinases are essential for the regulation of cellular proliferation, apoptosis, and migration as well as processes such as the growth of new blood vessels and axonal processes in the nervous system. Embryonic Determination and Differentiation DNA Methylation and Silencing of Genes Class Assignment 1. List the genes you know that are involved in different stages of embryonic development such as Compaction, Implantation, Gastrulation, Notochord formation, Neurulation and Limb formation. 2. List the anomalies that may arise from mutations of identified genes in (1) above.