7. Embryology-Early Development- Week 2-4 - I and II_Kubalak_NOTES.pdf

Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Embryology: Early Development I and II, Weeks 2-4 Steven W. Kubalak, PhD Department of Regenerative Medicine and Cell Biology Basic Science Building (BSB), Room 615C Email: [email protected] Office Phone: 2-0624 Lecture outline I....

Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Embryology: Early Development I and II, Weeks 2-4 Steven W. Kubalak, PhD Department of Regenerative Medicine and Cell Biology Basic Science Building (BSB), Room 615C Email: [email protected] Office Phone: 2-0624 Lecture outline I. II. III. IV. V. VI. VII. VIII. Introduction Week 2 of development a. Bilaminar Germ Disc b. Embryonic and Extraembryonic Mesoderm Formation c. Beginning of Uteroplacental Circulation Clinical Implications of Early Development Week 3 of development a. Gastrulation and Trilaminar Germ Disc b. Notochord Formation and Influence During Development c. Primitive Streak d. Neurulation and Neural Crest Formation e. Somite Development f. Formation of the Splanchnopleure and Somatopleure Early Development of Select Systems a. Blood Islands and Heart Formation b. Digestive system c. Chorionic Villi and Placentation Clinical Implications Detailed Germ Layer Derivatives Control of Organogenesis Reading Assignments: Text: Langman’s Medical Embryology, 14th ed. by Sadler © 2018 Ch. 5, p. 59-71 Ch. 6, p. 72-95 Objectives 1. Describe the various phases in the development of the primitive uteroplacental circulation through formation of mature chorionic villi. 2. Identify the cellular contributions to the bilaminar embryonic disc. 3. Identify the extraembryonic cavities and membranes. 4. Describe a hydatidiform mole. 5. Discuss the process of gastrulation. 6. Describe the formation and role of the notochord. 7. Define the process of neurulation and the structures that form as a result of neurulation. 8. Describe how the primordial cardiovascular system develops 9. Discuss the process of folding 10. List the early germ layer derivatives 11. Be able to list the given derivatives of neural crest cells Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 INTRODUCTION Figure 5.1 Carlson 5e, 2014 Recall this image from the introductory lecture. These are the basic cell and tissue lineages in the mammalian embryo (including extraembryonic tissues, which do not become part of the embryo) (modified from Figure 5.1, Carlson 5e, 2014). Note the colors represented in the developing embryo: blue – ectoderm, red – mesoderm, and yellow – endoderm. These different cell lineages differentiate into specific cell types that in some cases can be a completely new and very different cell from when it began. In these instances, it is said that their phenotype changes. For example, some endoderm cells transform in mesoderm, which is a mobile type of cell that has a different phenotype from endoderm. Also note that this image has the added placement of extraembryonic mesoderm derived from the yolk sac endoderm in addition to mesoderm that is formed from the primitive streak (as was presented in the lecture slides), which is different from the image in the textbook. Therefore, extraembryonic mesoderm has two sources: from yolk sac endoderm and from primitive streak cells. The initial portion of this lecture will examine the formation of these various cell types in the context of the developing embryo and the associated non-embryonic (extraembryonic) tissues. Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 WEEK 2 OF DEVELOPMENT Fig Figure 5.10 The second week of development is often referred to as the “week of twos” because several groups of cells or tissues differentiate into two new groups of cells or tissues (this is shown in the above Figure 5.10). The trophoblast layer has already formed the cytotrophoblast and syncytiotrophoblast; the latter continues to invade the endometrial stroma. Cells of the embryoblast differentiate into two layers, the epiblast and the hypoblast, also called the bilaminar embryonic disc. The amniotic and chorionic cavities form. The amniotic cavity forms within the epiblast, while the chorionic cavity forms adjacent to the embryo in extraembryonic tissue (same area as the yolk sac in the above image). These are summarized below: Trophoblast → Blastocyst cavity → Embryoblast → Cytotrophoblast Syncytiotrophoblast Week 2 of development: Trophoblast → • Cytotrophoblast • Syncytiotrophoblast Blastocyst cavity → • Amniotic cavity • Chorionic cavity Embryoblast → • Epiblast • Hypoblast Amnionic cavity Chorionic cavity Epiblast Hypoblast Syncytiotrophoblast cells begin to produce human chorionic gonadotropin (hCG), which maintains the activity of the corpus luteum and forms the basis for early pregnancy tests. Circulating hCG is a signal to the body that a conceptus has implanted. It can be detected in the mother’s blood and urine within 1-2 days after implantation. hCG is produced by the syncytiotrophoblast and is detected in mother’s blood within 1-2 days after implantation (the basis for pregnancy tests) Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Cells from the yolk sac endoderm (also called exocoelomic membrane and parietal endoderm) and primitive streak give rise to the extraembryonic mesoderm, which surrounds the amnion and yolk sac. This is shown in Figure 5.2 on the previous page (orange/tan tissue adjacent to endoderm). Lacunae appear in the syncytiotrophoblast and form sites of mixing of maternal blood and secretions from eroding uterine glands (labeled as trophoblastic lacuna in the Figure 5.10). At this early stage in development, nutrients pass to the embryonic disc by diffusion. Figure 5.10 This is the beginning of uteroplacental circulation or perhaps more appropriately called “communication” as there are no blood vessels yet. By day 10-12, the conceptus (embryo and associated membranes) is completely embedded in the endometrium and a closing plug is visible on the external surface of the endometrium. Several lacunae fuse and develop into lacunar networks (primordia of the intervillous space). Degenerated endometrial stromal cells and glands, together with maternal blood provide a rich source of embryonic nutrition. By day 12-12.5, lacunar networks continue to develop during establishment of the primitive uteroplacental circulation. The embryonic disc increases only minimally in size compared to the growth of the trophoblast and surrounding structures. As the overall conceptus increases in size, much of the growth is due to the development of the Figure 5.12 extraembryonic coelom from extraembryonic mesoderm. Shortly after its formation, extraembryonic coelom splits the extraembryonic mesoderm into the somatic and splanchnic mesoderm layers (these layers are not labeled in Figure 5.10 or 5.12). Importantly, primary chorionic villi begin to appear as cellular extensions from cytotrophoblast cell proliferation. Formation of these chorionic villi is induced by the underlying extraembryonic somatic mesoderm. Maturing chorionic villi will eventually become the fetal-maternal circulatory system within the placenta. The extraembryonic somatic mesoderm and the two layers of trophoblast constitute the chorion, which is the gestational sac within which the embryo is suspended by the connecting stalk. A specialized region of epiblast cells in the bilaminar germ disk forms the prechordal plate, this marks the cranial end of the embryo. Nutrients pass to the conceptus by diffusion until blood vessels are formed and circulation begins – which is around day 22 when the heart first starts to beat. Chorionic villi continue to develop (see next page) Chorion composed of: • Extraembryonic somatic mesoderm • Cytotrophoblast • Syncytiotrophoblast Embryo: • Bilaminar o Epiblast o Hypoblast Prechordal plate (specialized region of columnar epiblast cells) marks the cranial end of the germ disk Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 By Day 13, the extraembryonic coelom surrounds both the yolk sac and the amnion, except at the connecting stalk. With the development of the extraembryonic coelom, the yolk sac cavity decreases in size. Note the continued development of the chorionic villi all the way around the embryo at this age (Figure 5.12 previous page). Figure 5.11 (at left): Primary chorionic villi are composed of cytotrophoblast cells. Secondary chorionic villi are cytotrophoblast cells with an extraembryonic mesodermal core Figure 5.11 Tertiary chorionic villi have blood vessels present in the mesodermal core Clinical Implications Low HCG High HCG The production of human chorionic gonadotropin (hCG) by the syncytiotrophoblast is a critical component of pregnancy. It stimulates progesterone by the corpus luteum as mentioned earlier, and can be assayed in the blood (day 8 after fertilization) or urine (day 10) shortly after implantation. Low hCG levels can indicate spontaneous abortion or ectopic pregnancy while high hCG can suggest multiple pregnancies, hydatidiform mole, or gestational trophoblastic neoplasia. hCG is produced by the syncytiotrophoblast and is detected in mother’s blood within 1-2 days after implantation. • Blood day 8 • Urine day 10 Hydatidiform Mole “hydatid” Greek hydatidos, drop of water. Also called a molar pregnancy Forms(2) This structure is basically the over development of trophoblastic tissues along with the underdevelopment of the embryo. The result is a fluid-filled sac or mass of tissue that has no viable embryo. There are two forms of hydatidiform moles, complete and partial. Complete can be the result of: 1) preferential development of the trophoblast rather than the embryoblast 2) pregnancy without an embryo 3) placental villi becoming swollen and vesicular 4) trophoblastic tissue secreting abnormally high levels of hCG 5) the embryo being diploid but containing only paternal chromosomes 6) the female pronucleus becoming lost or absent 7) polyspermia 8) diploid sperm These typically result in the pregnancy becoming spontaneously aborted. Partial hydatidiform moles usually demonstrate some evidence of embryonic development and could result from 1) triploidy with a double dose of paternal chromosomes 2) polyspermia 3) diploid sperm These, too, typically spontaneously abort during the second trimester. Hydatidiform Mole • Also called Molar Pregnancy • Development of trophoblastic tissue without a normal embryo • Abnormally high hCG • Complete o “Complete” absence of embryonic tissue o Diploid but, chromosomes are paternal o Female pronucleus lost • Partial o Evidence of embryonic development, though abnormal: i.e. “Partial” embryo o Triploidy o Extra paternal chromosomes Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 WEEK 3: GASTRULATION Figure 2.9 Netter’s Atlas of Human Embryology, 2012 Def Gastrulation is the process by which the bilaminar embryonic disc is converted into a trilaminar embryonic disc and marks the beginning of morphogenesis. The process begins with the formation of the primitive streak at the caudal end of the embryo (Figure 2.9, above, from Netter’s Atlas of Human Embryology, 2012). Cells of the epiblast undergo an epithelial-mesenchymal transformation (EMT; this is a conversion of phenotype of the cells involved) and invaginate between the epiblast and hypoblast all along the primitive streak (curved arrows in below Figure 5.2. Figure 5.2 Begin date Gastrulation results in the generation of the three germ layers, ectoderm (blue), mesoderm (red), and endoderm (yellow). These can be seen in Figure 5.2. Gastrulation starts at the beginning of the third week (day 14). Gastrulation is the process by which the bilaminar embryonic disc is converted into a trilaminar embryonic disc and marks the beginning of morphogenesis. Gastrulation is epithelialmesenchymal transformation (EMT) of epiblast cells through the primitive streak forms all three germ layers (thus, all tissues). The standard color designation is the following: • Ectoderm (blue) • Mesoderm (red) • Endoderm (yellow) Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 The primitive streak actively forms mesenchyme until the early part of the fourth week. It then diminishes in size and becomes an insignificant region in the embryo and disappears by the end of the fourth week (this is a clinically significant event as we will see at the end of this lecture). Notochordal process • A mesodermal tissue • Extends from primitive pit to prechordal tissue • Precursor to notochord Notochord is an extremely important structure: • defines the primordial axis of the embryo and gives it some rigidity • serves as the basis for development of the axial skeleton (bones of the head and vertebral column) Figure 5.3 As the primitive streak continues to expand and elongate, the notochordal process develops from invaginating mesenchymal cells along the central axis of the embryonic disc (black region in Figure 5.3 above). These cells migrate cranially and also form around the prechordal mesoderm (prechordal plate). Recall that mesoderm is forming in all directions from the primitive streak. Overlying ectoderm is induced by the developing notochord to form a specialized neural tissue called neural plate. Shown above are sagittal (Panel A) and transverse (Panel B,C) views of the developing notochordal process (Figure 5.3). The notochordal process continues to expand toward the prechordal plate (beginning at the primitive pit and progressing toward the left in the image). Notice also the thickening of the overlying ectoderm (neural plate). The oropharyngeal (future mouth) and cloacal (future anus) membranes have no intervening mesoderm. As the notochordal process reaches the prechordal plate, perforations in the ventral side of the notochordal process form and spread through the endoderm in this region (middle panel). This results in the temporary continuity of the notochordal plate and the embryonic endoderm. It also results in the formation of the neurenteric canal (Panel A) and allows for communication between the amnionic and yolk sac cavities. The continuity between the notochordal process and the endoderm is short-lived. Infolding of the notochordal process forms the notochord while the endoderm fuses to again form a continuous layer. • indicates the future site of the vertebral bodies • induces the overlying embryonic ectoderm to thicken and form the neural plate • forms the nucleus pulposus in the adult, and • specifies cells in the ventral aspect of the neural tube Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 NEURULATION AND NEURAL CREST Primitive streak, if not completely degenerated, leads to sacrococcygeal teratoma. Figure 5.11 Carlson 5e, 2014 Note the relationship between the neural plate and the primitive streak (Figure 5.11 above); they do not overlap each other. Also note that the primitive streak eventually regresses until it completely disappears by the end of the fourth week. Neurulation is the processes involved in the formation of the neural plate and neural folds and closure of these folds to form the neural tube (see Figure 6.2 and 6.3 below). The neural plate (neuroectoderm) is formed by inductive influences of the underlying notochord and gives rise to the CNS – the brain and spinal cord. A neural grove and lateral neural folds become prominent at the cranial end of the embryo. These are the first signs of brain development. Neurulation is the processes involved in the formation of the neural plate and neural folds and closure of these folds to form the neural tube. Neural tube forms the CNS: • Brain • Spinal cord Figure 6.2 and 6.3 Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 You are responsible for the neural crest cell derivatives listed below. They will be covered in the embryology component of the curriculum – you will hear about them again as we cover each of the corresponding systems. Derivatives(9) • Ganglia – dorsal root ganglia, cranial nerve ganglia, and autonomic ganglia • Schwann cells – ensheathing cells of the peripheral nervous system • Enteric (gut) nervous system – regulates peristalsis, enzyme secretion • Chromaffin cells (adrenal medulla) – release Epi and NE • Parafollicular C cells of thyroid – release calcitonin to regulate Ca2+ Figure 3.3 From Netter’s Atlas of Human Embryology, 2012 • Melanocytes – pigment cells of the dermis By the end of the third week, the neural folds have begun to fuse, converting the neural plate into a neural tube. The newly formed neural tube soon separates from the surface ectoderm and the free edges of the ectoderm fuse (Figure 3.2 and 3.3 above from Netter’s Atlas of Human Embryology, 2012). • Aorticopulmonary septum – development of the septum between the aortic and pulmonary valves As the neural folds fuse to form the neural tube, some neuroectodermal cells laying along side the crest of each neural fold transform into a mesenchymal phenotype (Figure 3.2 and 3.3 at right). These will become the neural crest cells. These neural crest cells (NCCs) migrate dorsolaterally on each side of the neural tube and move within the mesenchyme of the embryo in various directions contributing to a wide variety of structures (see partial list below). (NCCs are so extremely important during the development of the embryo that there is a whole chapter in your textbook devoted just to NCCs: Chapter 12). • Pharyngeal arch skeletal components – muscle, connective tissue, bone • Bones of neurocranium – that part of the skull enclosing the brain Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 MESODERM Intraembryonic mesoderm forms: • Paraxial mesoderm • Intermediate mesoderm • Lateral mesoderm Figure 6.8 As neurulation is taking place, the intraembryonic mesoderm proliferates to form three regions of mesoderm: 1) paraxial 2) intermediate 3) lateral The paraxial mesoderm differentiates and begins to divide into paired cuboidal bodies (condensed mesenchyme), the somites. About 38 pairs of somites form during the somite period of development (days 20 to 30). By the end of the fifth week, 42 to 44 pairs of somites are present. The somites first appear in the future Figure 6.11 occipital region and develop in a cranial to-caudal direction, giving rise to most of the axial skeleton (bones of the cranium, vertebral column, ribs, and sternum) and associated musculature as well as the adjacent dermis of the skin. Somites form from paraxial mesoderm Somite (paraxial mesoderm) differentiation: Dermatome → • Dermis • Blade of the scapula Myotome → • Muscles of the back • Limb muscles • Muscles of the body wall • Sclerotome → • Axial skeleton (vertebrae and ribs) • Dura mater • Blood vessels of meninges Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Further differentiation of somites: At day 24 of development, the condensed mesenchyme differentiates into the dermomyotome and sclerotome. By day 26, the dermomyotome gives rise to separate regions, the dermatome and myotome (Figure 6.11 previous page). Lateral to the somites (paraxial mesoderm) is the intermediate mesoderm. Intermediate mesoderm gives rise to the urogenital system and will be discussed later in the renal and reproductive system lectures. Figure 6.8 In the most lateral position in the developing embryo is the lateral plate mesoderm, which is divided into two regions, somatic mesoderm and splanchnic mesoderm. Somatic mesoderm and the overlying ectoderm are referred to as the somatopleure and form the embryonic body wall. Splanchnic mesoderm and the underlying endoderm are called the splanchnopleure and form the embryonic gut wall. This particular mesodermal tissue gives rise to most of the cardiovascular system, including the heart. Intraembryonic somatic and splanchnic mesodermal layers are in continuity with the extraembryonic mesoderm that lines the amnion and yolk sac, respectively. Intermediate mesoderm differentiation: • Renal system • Reproductive system Lateral mesoderm differentiation: • Somatic mesoderm - body wall structures and associated blood vessels • Splanchnic mesoderm - Heart - Blood vessels of GI Figure 7.1 Because the embryo is undergoing folding during this time (days 21-28), the intraembryonic coelom (embryonic body cavities) and extraembryonic coelom begin to take shape. The primordia of the intraembryonic coelom appear as small, isolated coelomic spaces in the lateral mesoderm and cardiogenic mesoderm. It is the coalescence of these spaces that forms a horseshoe-shaped cavity, the intraembryonic coelom, which divides the lateral mesoderm into two layers, a parietal or intraembryonic somatic mesoderm and a visceral or intraembryonic splanchnic mesoderm. As development proceeds, the intraembryonic coelom ultimately forms the pericardial cavity, pleural cavity, and peritoneal cavity. Intraembryonic coelom • Pericardial cavity • Pleural cavity • Peritoneal cavity Extraembryonic coelom Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 EARLY STAGES OF THE CIRCULATORY SYSTEM Figure 6.19, Carlson 5e, 2014 Early development of the cardiovascular system begins with the formation of blood vessels and blood islands at about day 17 of development. This card devt occurs in the extraembryonic mesoderm of the yolk sac, connecting stalk, and chorion. Remember these are not structures within the embryo itself, -day that is, they are extraembryonic. Sources of extraembryonic blood cells: Yello CeCe 1. Yolk sac 2. Connecting stalk 3. Chorion -formation Vasculogenesis is formation of blood vessels from hemangioblasts, cells that have differentiated from the splanchnopleuric mesoderm. This is represented in the above figure and represents formation of new blood vessels where there were previously none (Figure 6.19 from Carlson 5e, 2014). These are also examples of epithelial-mesenchymal transformation (EMT) and mesenchymal-epithelial transformation (MET). In this case, MET occurs first and is the transformation of mesenchymal cells (cells of the mesoderm) into epithelial cells (the endothelium of newly formed blood vessels). This is followed by EMT, which is the transformation of some of the endothelial cells into circulating blood cells, which are considered a type of mesenchymal cell. The two processes (EMT and MET) occur in many different regions of the developing embryo and are crucial for proper tissue morphogenesis. Embryonic blood forms from mesoderm, chiefly in the liver, and later in spleen, bone marrow, and lymph nodes. Mesenchymal cells surrounding the primordial blood vessels differentiate into the muscular and connective tissue elements of the vessels. Through the end of the second week, embryonic nutrition is obtained from the maternal blood by diffusion through the yolk sac and extraembryonic coelom. During the third week a primordial uteroplacental circulation develops. Blood formation in the embryo does not begin until weeks 5-6. Blood cells in the embryo prior to this time originate in extraembryonic blood islands in specific regions of extraembryonic tissue. Do you recall where? Vasculogenesis should be contrasted to angiogenesis, which is budding and sprouting of new vessels from existing angioblastic cords. This represents formation of new blood vessels from preexisting vessels. A prime example of angiogenesis is the formation of much of the vasculature in the limbs. Vasculogenesis is the process of formation of blood vessels de novo (from the beginning) from hemangioblasts Angiogenesis is the process of formation of blood vessels from pre-existing vasculature Within the mesoderm, both MET and EMT are involved in forming blood vessels and blood cells. - MET → epithelium - EMT → blood cells Blood islands begin forming at approximately day 17 Blood cells not made by embryo until weeks 5-6 Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 HEART FORMATION Early stages of heart formation begin with the formation of the cardiogenic mesoderm, also called the cardiac crescent or cardiogenic plate (Figure 6.14) and is the primary heart field. The cardiac crescent forms paired regions of heart tubes that fuse in the midline and generate a single heart tube. A secondary heart field (green) contributes cells that form most of the outflow tract and right ventricle. The identification of specific regions of the early heart can be “matched” to the mature structures of the fourchambered heart. Folding in the transverse and sagittal planes is responsible for Figure 6.14 Carlson 5e, 2014 bringing together the paired heart tubes to form the single heart tube in its final orientation, which is ventral and caudal to the foregut. Early heart is a cardiac crescent Primary heart field: • Left ventricle Secondary heart field: • Outflow tract • Right ventricle Folding is caused by differential growth of neural tissue Folding in sagittal plane results in heart relocating to ventral and caudal location Figure 6.17 The above Figure 6.17 shows mid-sagittal sections. Note originally the cardiogenic plate is cranial to the neural plate. Differential growth of the neural tissue brings the heart ventral and caudal. This differential growth also occurs in the caudal region of the embryo and together with the differential growth in the cranial region results in folding of the embryo in two planes – transverse and sagittal. Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Folding converts the cardiac crescent to a single heart tube. Figure 13.5 The images in Figure 13.5 and 13.7 show the early development of the heart tube from two different perspectives. The images in Figure 13.5 are transverse sections (i.e. cross sections) and the images in Figure 13.7 are ventral views, which are analogous to coronal. Note that blood flow is unidirectional from the atrial regions to the ventricular regions. Also note in the below image that the heart begins to loop to the right, which is an important process that depicts the direction that the adult heart apex faces – i.e. to the left. AVT Blood flow is unidirectional and enters the ventrally located atrial region, travels up through the ventricular region, then out the truncus arteriosus region of the heart tube. Looping of the heart tube to the right leads to the left-sided apex in the adult heart. Heart beat #days Figure 13.7 You will learn much more details about heart development in the cardiovascular lectures. For now, it is important to know that it is occurring around 20 days of development and that at around 22 days, the heart begins to beat (immediately after the heart tube forms). The embryo is only about 23 mm in size – amazingly small for to have a beating, functioning heart! Note the relationship of the pericardial coelom and the developing heart tube. Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Mesodermal cells(5) Several different types of mesodermal cells contribute to the adult heart including: • Endocardial cushion cells • Endocardial endothelial cells • Ventricular and Atrial myocytes (muscle cells) • AV conducting cells • Purkinje fibers PAVEE Figure 6.18 Carlson 5e, 2014 Cells that migrate into the heart, also called extracardiac cells: FEES Proepicardial-derived cells • Epicardium • Endothelial cells of the vasculature (coronary arteries) • Smooth muscle cells of the vasculature (coronary arteries) • Fibroblast cells Figure 6.18 Carlson 5e, 2014 Cardiac neural crest cells • Smooth muscle cells of the great vessels • Parasympathetic neurons • Sympathetic neurons SPS Altogether, by day 20-22 when the heart starts to beat, an entire functioning vascular network has now been formed (Figure 6.26). Figure 6.26 Carlson 5e, 2014 Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 DIGESTIVE SYSTEM The tubular GI tract forms as a result of folding in the transverse and sagittal planes. The epithelial lining and associated glandular tissue of the GI tract is derived from endoderm Endoderm der.(7) Figure 15.1 Also forming as a result of folding during the third week is the digestive system, which is derived from endoderm (Figure 15.1). Folding in both the sagittal and transverse planes results in the establishment of foregut, midgut, and hindgut structures (colored yellow in the figure). Remember that these structures are forming in three dimensions. Thus, a tube-like shape is emerging for the gastrointestinal (GI) tract. Note that there remains a connection to the yolk sac through the vitelline duct. The vitelline duct is also called the yolk stalk or omphalomesenteric duct. The allantois appears on about day 16 as a small diverticulum (outpouching) from the caudal wall of the yolk sac (endoderm) and extends into the connecting stalk. The allantois is involved with early blood formation in the human embryo and is associated with development of the urinary bladder. As the bladder enlarges the allantois becomes the urachus, which is represented in adults by the median umbilical ligament. The blood vessels associated with the allantois become the umbilical arteries and veins. Notice at the cranial and caudal ends of the GI tract are two regions that are represented by an ectoderm-endoderm bilayer called the oropharyngeal membrane and cloacal membrane, respectively. These regions will eventually form the mouth (stomodeum) and anus (proctodeum). The primitive endoderm will also give rise to the: • Salivary glands • Thyroid • Lungs • Pancreas • Gallbladder • Liver • Allantois Allantois is involved in early blood formation and the development of the bladder Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 CHORION AND PLACENTA Figure 7.4 Carlson 5e, 2014 A critical extraembryonic circulatory component is the developing chorionic villi. We first saw the early chorionic villi in Figure 5.10. The chorionic villi are critical because they contribute the fetal component of the placental circulation. The above image (Figure 7.4) shows a timeline of the development of the chorionic villi. Primary chorionic villi can appear as early as day 11 as cytotrophoblastic proliferations that bud into the overlying syncytiotrophoblast. Shortly after primary chorionic villi appear, mesenchyme from the extraembryonic somatic mesoderm grows into the core, at which time they are referred to as secondary chorionic villi. Secondary chorionic villi form around the entire chorionic sac. Once some of the mesenchyme differentiates into capillaries and visible blood vessels they are referred to as tertiary chorionic villi (toward the end of the third week of pregnancy). These capillaries fuse to form arteriocapillary networks, which soon become connected with the embryonic heart via differentiated mesenchyme in the core of the chorion and connecting stalk. An alternative set of developmental examples is shown in the figure at right from Larsen’s Human Embryology, 3rd ed. 2001. This figure also shows nicely the anchoring villi, which are those villi that extend all the way to the trophoblastic shell, which is adjacent to maternal tissue. Therefore, the trophoblastic shell is made of anchoring villi and extravillous trophoblast cells (cytotrophoblast cells). These extravillous trophoblast cells breakdown maternal spiral arteries to allow bathing of the fetal placenta and its tertiary villi with maternal blood. Primary chorionic villi: • Cytotrophoblastic cells only Secondary chorionic villi: • Cytotrophoblast cells with extraembryonic mesodermal core Tertiary chorionic villi: • Mesodermal core has formed blood vessels Cytotrophoblast extends to maternal tissue and forms a shell around fetal component of placenta Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Umbilical arteries (two): • Carry O2-poor blood to placenta • Waste products from fetus to mother Figure 7.10 Carlson 5e, 2014 Arteries carry oxygen-poor blood and waste products away from the fetus and veins carry oxygen-rich blood and nutrients to the fetus. Note that the placental membranes become very thin at full term to allow for gas exchange. Above is a schematic drawing of a transverse section through a full-term placenta showing the relationship between fetal and maternal structures (Figure 7.10). Each section in the above image focuses on a different aspect of the placenta. In other words, selected structures have been removed in order to show each of the specific features labeled in the image. The three main functions of the placenta include • metabolism (for example synthesis of glycogen), • transport of gasses and nutrients • endocrine secretion (for example hCG) Waste products include CO2, water, urea, uric acid, and bilirubin. Just as nutrients are delivered to the fetus, so too are harmful substances such as certain drugs (e.g. alcohol) and viruses. This is schematically shown at right (Figure 7.14). Figure 7.14 Carlson 5e, 2014 Umbilical vein (one) • Carry O2-rich blood to fetus • Nutrients from mother to fetus Main functions of placenta: • metabolism (for example synthesis of glycogen), • transport of gasses and nutrients • endocrine secretion (for example hCG) Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 CLINICAL IMPLICATIONS 1 Sacrococcygeal teratoma is a tumor arising from remnants of the primitive streak. It often contains various kinds of tissues (e.g. bone, nerve, hair) and is more commonly in female infants. It usually becomes malignant and must be removed by 6 months of age Sacrococcygeal teratoma from remnants of primitive streak. The image to the right is a female infant with a large sacrococcygeal teratoma that developed from remnants of the primitive streak. The tumor, a neoplasm made up of several different types of tissue, was surgically removed. About 75% of infants with these tumors are female; the reason for this preponderance is unknown. (Courtesy of A.E. Chudley, MD, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children's Hospital and University of Manitoba, Winnipeg, Manitoba, Canada.) 2 Neural Tube Defects are disturbances in neurulation leading to abnormalities in the brain and spinal cord. They occur in 16 per 10,000 births in the eastern United States. The term anencephaly is commonly used, but the brain is not completely absent. The primary disturbance usually affects the neuroectoderm and results in failure of the neural tube to fuse. Neural tube defects from disturbance in neurulation. Can be cranial or caudal. Can be circumvented by folic acid supplementation. Although the neural folds may fail to neurulate in almost any region, the most frequent sites are the cranial and caudal neuropores. In the cranial region this results in the condition of craniorachischisis or anencephaly (A). Occasionally, more caudal regions of the neural tube may fail to form and differentiate, as in this case of inionschisis (B). (From Human Embryology, 3rd ed., Larsen WJ. 2001, Figure 4-20). 3 Caudal dysplasia (sirenomelia) is caused by abnormal gastrulation in which the migration of mesoderm is disturbed. Syndromes range from minor lesions of the lower vertebrae to complete fusion of the lower limbs (loss of mesoderm in the lumbosacral region). Caudal dysplasia from abnormal gastrulation Image from Langman’s Medical Embryology, 14th ed., Sadler TW. 2019, (Figure 5.8). 4 Fetal Alcohol Syndrome results from the passage of alcohol across the placental barrier. Note the thin upper lip, short palpebral fissures, flat nasal bridge, short nose, and elongated and poorly formed philtrum (vertical groove in the medial part of the upper lip). Image from The Developing Human, 8th ed., Moore and Persaud, 2008 (Figure 2017). Fetal alcohol syndrome from passage of alcohol across placenta Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 CONTROL OF ORGANOGENESIS All the major external and internal structures are established during the fourth to eighth weeks. By the end of this organogenic period, all the main organ systems have begun to develop; however, the function of most of them is minimal, except for the cardiovascular system. Much of this point forward will be spent increasing in size, undergoing various morphogenic changes and continued differentiation of tissues. Major structures formation(wks) Because tissues and organ systems are developing rapidly during this time, exposure of embryos to teratogens may cause severe congenital anomalies. Teratogens act during the stage of active differentiation of a tissue or organ and the most vulnerable period for the embryo is from the third to eighth weeks of development. Most developmental processes depend upon a precisely coordinated interaction of genetic and environmental factors. Several control mechanisms guide differentiation and ensure synchronized development such as: • controlled proliferation • programmed cell death (apoptosis) • cell migration • tissue interactions • extracellular matrix production Multiple processes guide differentiation: • Controlled proliferation • Programmed cell death (apoptosis) • Cell migration • Tissue interactions • Extracellular matrix production Early in development cells are basically pluripotential, able to follow more than one pathway of development. Cell fate decisions are determined by the cell’s surroundings, i.e. the cues that the cell is exposed to in its immediate environment. A recurring theme in development is that one cell lineage influences its neighbor through • the release of a diffusible substance • deposition of extracellular matrix • cell-cell contact initiating a response Multiple factors influence cell fate decisions: • Diffusable substances • ECM • Cell-cell contacts initiating a response Figure 6.21 CCPET Kubalak – 2022-2024 Embryology: Early Development I & II, Weeks 2-4 Figure 6.27 (Carlson 5e, 2014). A reminder of where we are going!! Take a look at the structures in the colored boxes. Then, follow the arrows outward to review how much we covered thus far.