V. ANAT 212 (Embryology) Group 1 - Reporting Handouts PDF

**GROUP 1 -- REPORTING HANDOUTS** **INDICATIVE CONTENT:** Cardiovascular system - - - - - Embryological and post-natal features of haematopoiesis - - - - - - Nervous system - - - - - - - - - - - - - - - - - I. - - - - -...

**GROUP 1 -- REPORTING HANDOUTS** **INDICATIVE CONTENT:** Cardiovascular system - - - - - Embryological and post-natal features of haematopoiesis - - - - - - Nervous system - - - - - - - - - - - - - - - - - I. - - - - - - - **Blood vessel formation** Occurs in two sequential steps: **Vasculogenesis** and **Angiogenesis** 1. - - a. - b. The contribution of haemangioblasts to the formation of blood vessels and to haematopoiesis is outlined in Fig. 11.1. 2. - - - **Development of blood vessels** involves a complex series of events during which endothelial cells **differentiate, proliferate, migrate** and **become organized** into an **orderly vascular network.** **Splanchnic mesodermal cells** - - - **Primitive Circulatory System** is the network of blood vessels and heart that forms early in an embryo\'s development. - - - - - - - - - - At first, the haematopoietic islands are compact structures. Later, cells at the periphery of the blood islands change their shape under the influence of growth factors and become squamous, enclosing the centrally-located cells. The squamous cells form the endothelial lining of the emerging vascular system and the rounded centrally- located cells become the haemoblastic cells or embry- onic nucleated erythrocytes (Fig. 11.2). - - -  **Vascular development** occurs under the **influence of specific growth factors**. - - - - - - -  **Development of the cardiac tubes** **3rd week of gestation** - - - - **Small discrete spaces** in the **left and right lateral mesoderm enlarge and coalesce**, forming a **left and a right intra-embryonic coelom**, thereby **splitting the lateral mesoderm** into: **parietal and splanchnic layers**. Later, the **coelom on the right and the coelom on the left fuse cranial to the developing neural plate**, forming an **enlarged horseshoe-shaped coelomic cavity** (Fig. 11.4). Ventral to the coelom, **groups of cells in the splanchnic mesoderm** form the **cardiogenic plat**e which is also **horseshoe-shaped**. Within the cardiogenic plate, **angiogenic cell clusters give rise to a horseshoe- shaped structure, the endocardial tube.** The **lateral limbs of the horseshoe-shaped vessel form the left and right endocardial tubes. Splanchnic mesodermal cells**, which **migrate towards and surround the endocardial tubes**, form the **myoepicardial mantle.** **Myoepicardial mantle** - The **intervening space** contains a **loose, gelatinous reticulum** referred to as **cardiac jelly.** Many of the **major intra-embryonic blood vessels**, including the: **Dorsal aortae** - - -  The **caudal rotation of the developing heart is accompanied by rapid growth of the brain** in an **anterior direction so that it extends over the cardiac area**. As a consequence of the **rotation**, the **convex segment of the fused endocardial tubes**, which initially occupied a position at the **anterior margin of the embryonic disc**, becomes positioned **caudal to the brain**. In this position, the **convex segment of the fused endocardial tubes anastomoses (aconnection that is created between tubular structures, such as blood vessels or loops of intestine) with the vitelline veins from the yolk sac** (Fig. 11.6). As a result of the folding of the cranial portion of the embryo, the **septum transversum (a sheet of mesodermal tissue that forms in an embryo and gives rise to parts of the diaphragm and ventral mesentery)** occupies a position **caudal to the heart** where, **at a later stage, it gives rise to the tendinous part of the diaphragm**. Before joining the convex segment of the endocardial tube, the **vitelline and umbilical veins pass through the septum transver- sum. The cranial portions of the dorsal aortae, which are drawn ventrally, form dorso-ventral loops. These loops, the first aortic arch arteries, fuse with the endo- cardial tubes** (Fig. 11.6).  With lateral folding of the embryo, the **left and right endocardial tbes**, surrounded by their **muscular layers**, **gradually approach each other**. Fusion of the **medial walls of the endocar- dial tubes first occurs midway along their length.** Later, **fusion extends cranially and caudally until a single cardiac tube is formed** (Figs. 11.6 and 11.7). However, as **fusion does not extend along the entire length of the endocardial tubes**, **the cranial and caudal ends remain separated**. The **endothelial lining of the single cardiac tube becomes the endocardium**, **the myoepicardial layer forms the myocardium,** and **from the visceral layer lin- ing the pericardial cavity the epicardium is formed.** The **cardiac tube, which is located in the pericardial cavity, is initially suspended by a dorsal mesocardium and anchored by a ventral mesocardium** (Fig. 11.7). **This cardiac tube undergoes differential growth along its length, which results in expanded portions separated by non-expanded portions. Listed in sequential order from the cranial end, these expanded portions are the truncus arteriosus, the bulbus cordis, the ventricle, the atrium and the sinus venosus (Fig. 11.8).** The **caudal end of the sinus venosus remains bifurcated.** The **ventral mesocardium persists for a short period only, unlike the dorsal mesocardium which persists for a longer time.** The dorsal mesocardium gradually breaks down leaving the primitive heart unattached, apart from its points of attachment to the pericardium at the truncus arteriosus and ventricle. At first, the atrium and sinus venosus are located outside the pericardial cavity in the septum transversum. Because the primitive heart increases in size faster than the pericardial cavity, especially in the bulbo-ventricular region, a U-shaped bend, the bulbo- ventricular loop, forms. As a consequence of this devel- opment the atrium and sinus venosus become drawn into the cavity (Fig. 11.8). The loop occupies a ventral position in the pericardial cavity, to the right of the medial plane. Further growth of the developing heart causes the atrium to occupy a position dorsal to the bul- bus cordis and ventricle, where it expands towards the truncus arteriosus. The sinus venosus is drawn into the pericardial cavity, and at this stage the developing heart becomes S-shaped (Fig. 11.8). A number of transcription factors have been implicated in the process of bulbo-ventricular loop formation. These include Hand-1 and Hand-2 transcription factors which are regulated by Nkx-2.5. As heart development proceeds, Hand-1 expression becomes confined to the developing left ventricle and Hand-2 to the developing right ventricle. Deletion of genes which encode Hand-1 or Hand-2 factors results in hypoplasia of the ventricle in which they are normally expressed. The T box factors, Tbf-5 and Tbf-20, together with Bmp-4, also influence the formation of the bulbo-ventricular loop. Differ- ential contraction of the actin cytoskeleton has been proposed as a determining factor in the formation of the bulbo-ventricular loop. During cardiac morphogenesis, blood vessel formation continues within the embryo. Two major blood vessels which form ventral to the neural tube become the left and right dorsal aortae. Cranially, they fuse with the left and right limbs of the endocardial tubes. Associated with the lateral folding of the embryo, the dorsal aortae caudal to the developing heart fuse, forming a common aorta. In the mesenchyme adjacent to the truncus arte- riosus, an additional series of paired aortic arch arteries develop which join the dilated end of the truncus arteriosus with the dorsal aortae (Fig. 11.8). Branches of the dorsal aortae, the intersegmental arteries, supply the developing somites. Additional branches supply the yolk sac through the vitelline arteries, and the umbilical arteries supply the allantois. Following the formation of the vitelline veins which drain the yolk sac, the umbilical veins which drain the allantois, the cranial cardinal veins draining the head and the caudal cardinal veins convey- ing blood from the body wall, venous blood is returned to the caudal end of the primitive heart, the sinus veno- sus (Fig. 11.3). On each side of the developing embryo, the cranial and caudal cardinal veins fuse, forming the common cardinal veins which enter the sinus venosus. At this precise stage of morphogenesis, the develop- ing mammalian cardiovascular system bears a strong resemblance, both morphologically and functionally, to that of the fully formed circulatory system of fish.  **Molecular aspects of cardiac development** The transcription factor Nkx-2.5 is central to the initial induction of splanchnic mesodermal cells which ultimately contribute to cardiogenic mesoderm formation. This transcription factor is up-regulated under the influence of Bmp and Fgf factors. Nkx-2.5 activates the synthesis of other transcription factors such as members of the GATA-4 and Mef-2 families. These transcription factors up-regulate the expression of cardiac-specific proteins, including cardiac actin and a-myosin. Left-right pat- terning proteins such as Nodal and Lefty-2 influence the pattern of asymmetry, a feature of heart formation. The transcription factor Pitx-2, which is up-regulated by Nodal, is critical for normal heart morphogenesis. **Formation of the cardiac chambers** Partitions which form in the primordial mammalian heart gradually convert the single pulsating cardiac tube into a complex four-chambered organ. Although formation of cardiac septa takes place at approximately the same time, for descriptive purposes their formation is described as if they were separate events. The foetal heart continues to function effectively as these ongoing major structural changes occur. *Partitioning of the atrio-ventricular canal* In the region of the atrio-ventricular canal, two masses of cardiac mesenchymal tissue known as endocardial cushions, which are located between the endocardium and the myocardium, extend towards each other and fuse. The fused endocardial cushions form the septum inter- medium, which divides the common atrio-ventricular canal into left and right atrio-ventricular openings (Fig. 11.9).  *Partitioning of the common foetal atrium* During proliferation of the endocardial cushions, a crescent-shaped fold, the septum primum, arises from the dorsal wall of the common foetal atrium and extends towards the endocardial cushions. The septum primum gradually divides the common atrium into a left and a right atrium (Fig. 11.10). As the septum primum grows towards the endocardial cushions, an opening, the fora- men primum, persists between the left and right foetal atria. This foramen gradually decreases in size and, when the septum primum reaches the cushions, it even- tually closes. Before closure of the foramen primum, however, programmed cell death in the central part of the septum primum results in the formation of a new communication channel between the left and right atria, the foramen secundum (Fig. 11.10). A second membrane, the septum secundum, arises from the dorsal wall of the right atrium, to the right of the septum primum, and extends towards the septum intermedium. The central portion of the septum secundum overlaps the foramen secundum, but does not extend as far as the septum intermedium. The opening which persists between the free edge of the septum secundum and the foramen secundum is known as the foramen ovale. The upper part of the septum primum fuses with the septum secun- dum while the remaining portion becomes a valve-like structure for the foramen ovale. The lower margin of the septum secundum divides the blood flow returning to the heart via the caudal vena cava into two streams. The greater amount is directed through the foramen ovale into the left atrium, while a lesser amount is directed through the right atrio-ventricular opening into the right ventricle. Due to its functional role, the lower margin of the septum secundum is appropriately named the crista dividens. At birth, the valve-like structure of the foramen ovale closes, completing the separation of the left and right atria. *Final form of the right atrium* In the early stages of cardiac morphogenesis, blood returning from the left side of the embryo enters the left horn of the sinus venosus. Blood from the right side of the embryo enters the right horn of the sinus. The venous blood entering the sinus venosus enters the embryonic atrium through the sino-atrial opening, which is regulated by the sino-atrial valve composed of left and right components. Development of venous shunts between the left and right systemic venous systems leads to the preferential direction of flow to the right side, resulting in enlargement of the right horn of the sinus venosus while the left horn decreases in size. As partitioning of the atrium proceeds, the sino-atrial opening occupies a position in the right half of the foetal atrium. Gradually, the right horn of the sinus venosus becomes incorporated into the right foetal atrium. In its final form, the right atrium consists of the right foetal atrium which becomes the muscular right auricle, while the right horn of the sinus venosus becomes the thin- walled sinus venarum into which the venous return from the body enters the heart (Fig. 11,11). During morpho- logical adaptation, the left portion of the sino-atrial valve fuses with the septum secundum, while part of the right portion forms an internal ridge, the demarcation between the auricle and the sinus venarum, termed the crista terminalis. On the external surface a depression, the sulcus terminalis, marks this division. The remainder of the right portion of the sino-atrial valve contributes to the formation of the valves of the caudal vena cava and coronary sinus. The regressing left horn of the sinus venosus contributes to the formation of the coronary venous sinus which opens into the right atrium. *Final form of the left atrium* The embryonic pulmonary vein develops as an out- growth of the left foetal atrium, to the left of the septum primum. The vein divides into left and right branches which supply the developing bronchial buds. Later, the left and right branches subdivide. In a manner similar to the incorporation of the right horn of the sinus venosus into the right atrium, the enlarged pulmonary vein and its branches become incorporated into the left atrium. Thus, four pulmonary veins are incorporated into the fully formed left atrium, two from each lung. The left atrium therefore comprises the left foetal atrium, which becomes the left auricle, and the integrated pulmonary veins, which form the smooth portion of the wall of this chamber (Fig. 11.11). *Formation of the left and right ventricles* Following its differential growth, the bulbus cordis con- sists of a dilated portion adjacent to the ventricle and a non-dilated portion referred to as the conus cordis, which is continuous with the truncus arteriosus. The dilated portion of the bulbus cordis and the embryonic ventricle form a common chamber. Externally, the divi- sion between the bulbus cordis and ventricle is marked by a groove, the inter-ventricular sulcus, and internally by a muscular fold, the primordial inter-ventricular septum (Fig. 11.10). As the walls of the ventricle and bulbus cordis increase in thickness, diverticulation of their inner surfaces imparts a trabecular appearance to the myocardium. At this stage, the embryonic ventricle can be considered as the primitive left ventricle and the dilated bulbus cordis as the primitive right ventricle. The ventricles enlarge by peripheral growth which is closely followed by increased diverticulation and tra- beculation of their inner walls. As the inter-ventricular sulcus deepens and the walls of the expanding ventricles meet medially at the sulcus, the walls become apposed and fuse, contributing to the elongation of the inter- ventricular septum. Continued peripheral growth of the myocardial tissue of each ventricle accounts for the progressive increase in length of the inter-ventricular septum. At this stage, the septum does not completely separate the two ventricles, which communicate through the inter-ventricular foramen. Later, as a consequence of differential cellular proliferation, the inter-ventricular foramen closes (Fig. 11.10).  *Partitioning of the conus cordis and truncus arteriosus* Two sub-endocardial thickenings, the bulbar ridges, which fuse forming the aortico-pulmonary septum, divide the conus cordis and truncus arteriosus into an aortic trunk and a pulmonary trunk (Fig. 11.12). The spiral form of the aortico-pulmonary septum ensures that the aortic trunk becomes continuous with the fourth aortic arch arteries and that the pulmonary trunk communicates with the sixth aortic arch arteries. Mesenchymal cells of neural crest origin, which migrate from the cranial region, contribute to the formation of the aortico-pulmonary septum.  *Closure of the inter-ventricular foramen* The developmental changes which lead to the closure of the inter-ventricular foramen are complex. The membranous portion of the inter-ventricular septum, which causes closure of the inter-ventricular foramen, is formed from proliferation of tissues derived from the bulbar ridges of the aortico-pulmonary septum, the sep- tum intermedium, and the muscular inter-ventricular septum (Fig. 11.13). Following closure, the pulmonary trunk carries blood from the right ventricle and the aortic trunk conveys blood from the left ventricle. *Formation of cardiac valves* The aortic and pulmonary valves, which are necessary for prevention of backflow of blood into the left and right ventricles, arise from three swellings of sub-endothelial mesenchymal tissue at the origins of the aortic and pul- monary trunks. Mesenchymal tissue of neural crest origin contributes to the formation of these valves. As a conse- quence of hollowing out, these ridges become re-modelled forming three thin-walled cusps, composed of folded endothelial tissue with connective tissue cores (Fig. 11.14). As the endocardial cushions fuse and divide the common atrio-ventricular opening into left and right openings, the left and right atrio-ventricular valves form at these openings. The left atrio-ventricular valve is composed of two cusps and is referred to as bicuspid, while the right atrio-ventricular valve is composed of three cusps and is referred to as tricuspid. Mesenchymal tissue proliferates around the rim of each orifice. Cavitation of the muscular layer immediately beneath the mesenchymal thickening, and re-modelling of the associated tissue, contribute to the formation of the cusps of the atrio-ventricular valves (Fig. 11.15). Because the valves are partially derived from mesenchymal tissue which was originally attached directly to the myocardium at the orifices, the valves remain anchored by muscular strands to the ventricular walls. With diverticulation and resultant thinning of the ventricular walls, muscular strands remain attached along the ventricular surface of the valve cusps. These thin muscular structures are gradually replaced by dense connective tissue, the chordae tendineae, which connect the valve cusps to muscular projections of the ventricu- lar walls referred to as papillary muscles (Fig. 11.15).  **Conducting system of the Heart** - - - - - - - - - **Development of the arterial system** 1. 2. a. 3. a. b. 4. a. b. 5. a. b. c. **Derivatives of aortic arch arteries** - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - **Branches of the Aorta** 1. a. b. c. 2. a. b. c. d. e. f. g. 3. a. 4. a. 5. a. **Development of the Venous System - Key Points:** - - - - - **Arterial and Venous Differentiation** 1. a. 2. a. b. 3. a. i. ii. **Vitelline Veins** 1. a. b. 2. a. b. 3. a. b. 4. a. i. ii. 5. a. b. c. **Umbilical Veins** 1. a. 2. a. i. ii. iii. 3. a. b. 4. a. 5. a. **Important Details on Cardinal Veins:** 1. a. b. 2. a. 3. a. i. ii. iii. 4. a. b. 5. a. i. ii. iii. 6. a. **Circulation Before Birth:** 1. a. 2. a. b. 3. a. 4. a. 5. a. 6. a. b. 7. a. 8. a. 9. a. **Circulation After Birth:** - - - **Circulatory Changes at Birth:** 1. a. 2. a. 3. a. i. ii. b. i. ii. iii. c. i. ii. iii. iv. d. i. ii. iii. **Lymphatic Vessels and Lymph Nodes:** 1. a. b. 2. a. b. c. d. 3. a. b. c. 4. a. b. c. 5. a. b. **Development of Lymph Nodes:** 1. a. b. 2. a. 3. a. b. 4. a. 5. a. i. ii. b. 6. a. b. **Adult Derivatives of Fetal Blood Vessels and Structures:** 1. 2. 3. 4. 5. 6. **Developmental Anomalies of the Cardiovascular System:** 1. a. b. 2. a. b. c. d. e. f. g. h. 3. a. b. c. d. 4. a. **Patent Ductus Arteriosus (PDA) - Key Points:** - - - - - - **Pulmonary Stenosis - Key Points:** - - - - - - **Aortic Stenosis - Key Points:** - - - - **Tetralogy of Fallot - Key Points:** - - - - - - - - **Inter-Atrial Septal Defects - Key Points:** - - - - **Inter-Ventricular Septal Defects - Key Points:** - - - - - **Abnormalities of the Position of the Heart - Key Points:** - - - - - - - **Congenital Venous Shunts - Key Points:** - - - - - - **Persistent Right Aortic Arch Combined with Left Ductus Arteriosus - Key Points:** - - - - - - **Aberrant Right Subclavian Artery - Key Points:** - - - - **Double Aortic Arch - Key Points:** - - - **Clinical Manifestations of Vascular Ring Anomalies - Key Points:** - - - - - - - - **II. EMBRYOLOGICAL AND POST-NATAL FEATURES OF HAEMATOPOIESIS** **Haematopoiesis** is blood cell production. The body continually makes new blood cells to replace old blood cells to have a steady blood supply. Hematopoiesis starts before birth and continues as a cycle throughout lif**e.** **Blood Cell Maintenance:** - - - **Neoplastic Conditions:** - **Embryonic Development:** - - **Haematopoiesis:** - - - - **Cell Differentiation and Maturation:** - - **Cell Lifespan and Replacement:** - **Embryonic Stem Cells:** - - **Post-natal Stem Cells:** - - **Function of Blood Cell Types:** - - - 1. - 2. - 3. - - 4. - - 5. - 6. - 7. - 8. - - 9. - 10. - **Spleen\'s Role in Late Fetal Life:** - **Bone Marrow as Primary Site in Adults:** - **Avian Haematopoiesis:** - - - **Human Embryonic Haematopoiesis:** - - **Human Yolk Sac and Early Haematopoiesis:** - - **Para-Aortic Region in Human Development:** - **Liver\'s Role in Human Haematopoiesis:** - - **Bone Marrow as Lifelong Haematopoietic Site:** - **HSC Homing and Microenvironment:** - - **Role of Growth Factors and Proteins in Haematopoiesis:** - - - - - **Signaling Pathways in Haematopoiesis:** - - **Haematopoietic Growth Factors:** - - **Mechanisms of Lineage Commitment:** - **Lymphoid and Myeloid Cell Maturation:** - **Cells or Formed Elements** **1. Basophils** Origin: Bone marrow Lineage: Myeloid Morphology: Lobed nuclei with large metachromatic granules Distribution: Blood Comments: Non-phagocytic, less than 1% of circulating white blood cells. Granules contain substances active in allergic reactions. **2. B Lymphocytes** Origin: Bone marrow Lineage: Lymphoid Morphology: Round or slightly indented nuclei Distribution: Blood and tissues Comments: Mature in bone marrow (mammals) or bursa of Fabricius (birds). Differentiate into antibody-producing plasma cells; some become memory cells. **3. Dendritic Cells** Origin: Bone marrow Lineage: Myeloid and lymphoid Morphology: Large cells with dendrite-like processes Distribution: Skin, organs, lymphoid tissue, blood, and lymph Comments: Key antigen-presenting cells for T lymphocytes; named by location, e.g., Langerhans cells in the epidermis. **4. Eosinophils** Origin: Bone marrow Lineage: Myeloid Morphology: Bi-lobed nuclei with acidic dye-affinitive granules Distribution: Blood and tissues Comments: Phagocytic cells with protective roles against parasites; involved in modulating inflammatory and hypersensitivity responses. **5. Erythrocytes** Origin: Bone marrow Lineage: Myeloid Morphology: Non-nucleated, flattened, bi-concave cells Distribution: Blood Comments: Oxygen transport cells with a lifespan of 120 days (humans); production regulated by erythropoietin, influenced by oxygen levels. **6. Macrophages** Origin: Bone marrow Lineage: Myeloid Morphology: Large mononuclear cells with irregular nuclei Distribution: Tissues throughout the body Comments: Formed from monocytes in tissues; named by location (e.g., Kupffer cells in liver). Long-lived phagocytes involved in pathogen destruction and antigen presentation. **7. Mast Cells** Origin: Bone marrow Lineage: Myeloid Morphology: Mononuclear cells with metachromatic granules Distribution: Connective tissue near blood vessels, nerves, and mucosal tissue Comments: Granules rich in histamine and heparin. Involved in immediate hypersensitivity reactions through IgE receptors and degranulation. **8. Monocytes** Origin: Bone marrow Lineage: Myeloid Morphology: Large cells with kidney-shaped nuclei Distribution: Blood Comments: Motile phagocytic cells that circulate briefly before migrating into tissues, where they differentiate into macrophages or dendritic cells. **9. Natural Killer (NK) Cells** Origin: Bone marrow Lineage: Lymphoid Morphology: Large granular mononuclear cells Distribution: Blood and peripheral tissues Comments: Non-specific immune cells that lack antigen-specific receptors. Target virus-infected and tumor cells, and participate in antibody-dependent cell-mediated cytotoxicity. **10. Neutrophils** Origin: Bone marrow Lineage: Myeloid Morphology: Multi-lobed nuclei with pale pink granules Distribution: Blood, migrating into tissues upon stimulation Comments: Short-lived, motile phagocytes (polymorphonuclear leukocytes) that destroy bacteria and other foreign particles. Granules contain enzymes like elastase, myeloperoxidase, and lysozyme. **11. Plasma Cells** Origin: Bone marrow Lineage: Lymphoid Morphology: Basophilic with prominent Golgi and endoplasmic reticulum, eccentric cartwheel-shaped nuclei Distribution: Connective tissue and secondary lymphoid organs (e.g., spleen, lymph nodes) Comments: Derived from B cells upon antigenic stimulation. Secrete antibodies and have a lifespan of up to 2 weeks. **12. Platelets** Origin: Bone marrow (from megakaryocytes) Lineage: Myeloid Morphology: Small cytoplasmic fragments Distribution: Blood Comments: Produced under the influence of thrombopoietin. Adhere to damaged blood vessels to initiate clotting. **13. T Lymphocytes** Origin: Bone marrow (mature in thymus) Lineage: Lymphoid Morphology: Round or slightly indented nuclei Distribution: Blood and tissues Comments: Includes cytotoxic (CD8+) and helper (CD4+) subsets. T cell receptors recognize antigens only when complexed with major histocompatibility complex (MHC) proteins. Cytotoxic T cells kill infected or abnormal cells; helper T cells enhance immune responses. 1. - 2. - - 3. - - - - - 4. 1. 2. 3. 4. 5. 6. 7. **III. NERVOUS SYSTEM** During the third week of embryological development in domestic animals, the notochord stimulates the ectoderm to form the neural plate, which is a spoon-shaped thickening. The cranial part of this plate develops into the brain, while the caudal part forms the neural tube. The lateral edges of the neural plate rise to create neural folds, and the midline forms a groove known as the neural groove. As development progresses, the neural plate folds into a V-shape, with cellular changes causing neuroepithelial cells to become wedge-shaped. This leads to the neural folds approaching and fusing in the midline, forming the neural tube that encloses the central neural canal. The closure of the neural tube begins at the level of the fourth somite and proceeds in both cranial and caudal directions, similar to a zipper. The ends of the neural tube, called the rostral and caudal neuropores, remain open for a time and allow nutrient exchange with the amniotic fluid The rostral neuropore closes midway through the embryonic period, followed by the closure of the caudal neuropore. After closure, the neural tube separates from the surface ectoderm and lies ventrally to it. This process, known as primary neurulation, encompasses the area between the rostral and caudal neuropores. In the sacral and caudal regions, neural tube formation occurs through secondary neurulation, where mesenchymal cells from the primitive streak fuse with the closed end of the neural tube. A central canal forms within this mesenchymal cord, connecting with the neural canal from primary neurulation. The length of the spinal cord region resulting from secondary neurulation varies with the number of caudal vertebrae, being longer in animals with long tails and shorter in higher primates. **Dorsal--ventral patterning of the neural tube**  Once the neural plate is induced to undergo neurulation by the mesoderm, the formation of the neural tube begins. This process is influenced by two key signaling centers: one in the ectoderm above and another in the notochord below. The roof plate of the neural tube receives signals from Bmp-4 and Bmp-7, while the floor plate is influenced by Shh signals from the notochord. As development progresses, secondary signaling centers form within the neural tube itself. Bmp-4 is secreted by the roof plate cells, and Shh is produced by the floor plate cells. These molecules create opposing gradients along the dorsal-ventral axis of the neural tube: Bmp-4 diffuses ventrally while Shh diffuses dorsally. Cells along this axis experience different concentrations of these signaling molecules, which affects the expression of transcription factors. Cells near the floor plate, exposed to high levels of Shh and low levels of Tgf-β, express Nkx6.1 and Nkx2.2, leading to their differentiation into ventral neurons. Conversely, dorsal cells, which receive low levels of Shh and high levels of Tgf-β, express different fate-determining transcription factors, guiding them toward different developmental paths **Neural crest** During the fusion of the neural folds, specialized cells known as neural crest cells emerge along the lateral margins at the interface between the neural plate and surface ectoderm. These cells are influenced by bone morphogenic proteins and Wnt-6, which lead neuroepithelial cells to adopt mesenchyme-like characteristics and penetrate the basal lamina of the neural plate. The presence of Wnt, Fgf proteins, Bmp-4, and Bmp-7 induces the expression of Slug and RhoB in these cells, both of which are believed to facilitate neural crest cell migration. RhoB may play a role in cytoskeletal changes that aid migration, while Slug activates factors that disrupt tight junctions between adjacent cells. As neural crest cells migrate, they down-regulate the cell adhesion protein N-cadherin. During migration, neural crest cells form segmental aggregations along the dorsal aspect of the neural tube. Their movement is influenced by the extracellular matrix, which contains proteins like fibronectin, laminin, tenascin, and certain collagens that promote migration, while ephrin proteins can inhibit it. Factors such as stem cell factor support the continued proliferation of these cells. **Differentiation of the cellular components of the neural tube** The neural tube is initially lined with pseudostratified columnar neuroepithelial cells that differentiate into two main cell types: neuronal progenitor cells (neuroblasts) and glial progenitor cells (gliablasts). Neuroblasts develop into neurons of the central nervous system, while gliablasts give rise to supporting cells. As differentiation progresses, the neural tube forms three distinct layers: an inner ependymal layer, a middle mantle layer, and an outer marginal layer. Neuroblasts, characterized by large round nuclei and prominent nucleoli, migrate outward from the ependymal layer to form the mantle layer, which ultimately becomes the grey matter of the spinal cord. The cytoplasmic processes of neuroblasts contribute to the marginal layer. Gliablasts differentiate into astrocytes (present in both the mantle and marginal layers) and oligodendroglia (mainly in the marginal layer). The neuroepithelium also gives rise to ependymal cells that line the brain ventricles and the central canal of the spinal cord. Microglial cells, which are phagocytic and of mesenchymal origin, enter the central nervous system after vascularization. In the mantle layer, neuroblasts in the dorsal and ventral regions proliferate, creating dorsal thickenings (alar plates) and ventral thickenings (basal plates). The alar plates become populated by neuroblasts that differentiate into interneurons, which relay sensory impulses, while the basal plates develop motor neurons. The sulcus limitans, a longitudinal groove, forms along the inner wall of the central canal, marking the boundary between the sensory and motor regions. As cell division accelerates, the alar and basal plates fuse, forming the characteristic butterfly-shaped grey matter in the spinal cord cross-section. The central canal decreases in diameter, and bilateral ventral bulging creates a deep medial groove, known as the ventral fissure. The dorsal roof plate and ventral floor plate of the neural tube do not contain neuroblasts but serve as pathways for crossing fibers. In the thoraco-lumbar region, neuroblasts in the basal plate form lateral horns, which contribute to the sympathetic division of the autonomic nervous system. Additionally, cells from the neural crest develop into dorsal root ganglia, serving as sensory components of the peripheral nervous system. **Spinal nerves** Neuroblasts in the basal plates of the neural tube differentiate into motor neurons, developing multiple short dendritic processes on one side and a single long axon on the opposite side. Neurons with multiple dendrites are classified as multipolar neurons. Axons extend from the spinal cord through the marginal layer into the vertebral canal, forming ventral roots that innervate effector organs. Sensory components of spinal nerves originate from neuroblasts in the dorsal root ganglia, which have two processes: one extending into the dorsal horn of the spinal cord and the other extending to sensory receptors in organs like the skin. In the dorsal horn, sensory nerve processes typically form synapses with interneurons, which can connect to either ipsilateral or contralateral ventral motor neurons, creating multi-synaptic reflex arcs. Occasionally, sensory processes may form direct synapses with motor neurons, resulting in mono-synaptic reflex arcs. Interneuron axons can either extend cranially to synapse at higher spinal cord levels or continue to brain nuclei. Spinal nerves consist of general somatic afferent and efferent fibers. The general visceral efferent system involves two neurons: pre-ganglionic fibers from the lateral horn of the spinal cord and post-ganglionic fibers from autonomic ganglia, which innervate smooth muscle, cardiac muscle, and glands. Autonomic ganglia develop from neural crest cells. Spinal nerves include a dorsal root with sensory fibers and a ventral root with motor fibers, which intermingle at the intervertebral foramen. Each spinal nerve divides into dorsal and ventral branches, both containing somatic and visceral fibers. The ventral branches in the cervical and lumbo-sacral regions form plexuses related to limb development. Certain regions of the spinal cord, such as the cervical intumescence (associated with thoracic limb innervation) and lumbar intumescence (associated with pelvic limb innervation), increase in size due to a higher number of neurons. Spinal nerves are named based on their emergence from the vertebral canal, with specific naming conventions for cervical nerves due to the presence of eight spinal nerves and only seven cervical vertebrae. A spinal cord segment corresponds to the spinal nerves that arise from it and is assigned a number based on the associated spinal nerves. **Myelination of peripheral nerve fibres** Schwann cells, which are derived from neural crest cells, play a crucial role in the myelination of peripheral nerve fibers. During myelination, these neurilemmal cells wrap around axons to form a myelin sheath. The classification of nerve fibers as myelinated or non-myelinated depends on how the neurilemmal cell interacts with the axon. If a neurilemmal cell surrounds a nerve fiber without wrapping deeply, the fiber is classified as non-myelinated. In this case, multiple nerve fibers can be enclosed by a single neurilemmal cell. Conversely, when a neurilemmal cell wraps around a single nerve fiber multiple times, creating concentric layers of its cytoplasm and plasma membrane, the fiber is classified as myelinated. During the myelination process, the cytoplasm of the neurilemmal cell is extruded, and the layered plasma membranes fuse together to form the myelin sheath. This sheath is essential for the proper functioning of nerve fibers, enhancing the speed of nerve impulse transmission. **Changes in the relative positions of the spinal cord and the developing vertebral column** Towards the end of the embryonic period, the spinal cord is the same length as the vertebral canal, with spinal nerves emerging from the vertebral column at corresponding levels. However, during the fetal period, the vertebral column grows faster than the spinal cord, leading to a situation where, in late fetal development, the spinal cord is significantly shorter than the vertebral canal. This results in the spinal cord terminating at different levels in the lumbo-sacral region across various domestic animal species. At this stage, few neurons develop in the caudal end of the spinal cord, which tapers to form a structure known as the conus medullaris. Below this, the terminal portion consists of a cord-like strand of glial and ependymal cells called the filum terminale, which anchors the conus medullaris to the caudal vertebrae. Due to the increased length of the vertebral canal compared to the spinal cord, the intervertebral foramina are positioned more caudally than the origins of the corresponding spinal nerves. Consequently, the roots of lumbar, sacral, and caudal spinal nerves must travel caudally within the vertebral canal before exiting through the intervertebral foramina at a distance from their origins. This arrangement of elongated nerve roots is collectively known as the cauda equina. **Anomalies of the spinal cord** Failure of the neural tube to close can result from improper induction by the underlying notochord or exposure to teratogenic factors that disrupt the normal differentiation of neuroepithelium. This defect can affect the entire length of the neural tube or be localized to a specific region, leading to adverse effects on the development of both the nervous system and the vertebral column. One consequence of neural tube closure failure is the disruption of vertebral arch induction, which can result in spina bifida---a condition characterized by an open vertebral canal. Spina bifida can cause motor and sensory deficits and may lead to severe clinical complications, including chronic infections. The severity of spina bifida varies, ranging from minor anomalies with little clinical significance to life-threatening conditions. A specific form of spina bifida, known as spina bifida occulta, typically occurs in the lumbo-sacral region and involves the failure of one or two vertebral arches to close, resulting in the dura mater being located under the skin. In this case, the spinal cord and nerve roots usually develop normally, and neurological symptoms are often absent. In humans, it may present as a tuft of hair over the affected area. If more than two vertebrae are involved and the dura mater ruptures, the meninges may herniate through the opening, creating a subcutaneous bulge filled with cerebrospinal fluid. If only the meninges and fluid herniate, it is termed meningocoele, which may show minor neurological signs and can be surgically repaired. If the spinal cord is displaced into the herniated area, the condition is known as meningomyelocoele, leading to potential damage to spinal nerve roots and varying neurological symptoms. Complete closure failure of the neural tube, referred to as rachischisis, is invariably fatal. Research suggests that fertilization of ova beyond the optimal time may increase the incidence of neural tube anomalies. Prenatal diagnosis of spina bifida can be achieved by detecting elevated levels of α-fetoprotein in amniotic fluid or through ultrasonography. **Differentiation of the brain sub-division** The cranial expanded region of the neural plate gives rise to three dilatations, the primary brain vesicles, namely the prosencephalon (fore-brain), the mesencephalon (mid-brain) and the rhombencephalon (hind-brain).In higher vertebrates, the compact nature of the brain and the relatively small space in which it develops are achieved through the formation of flexures and surface foldings as it is accommodated in the cranium.The ventral cranial flexure, which occurs in the mid-brain region, is known as the cephalic flexure.The flexure between the hind-brain and the spinal cord is termed the cervical flexure. - - - **Rhombencephalon** - - **Myelencephalon** - - - - **Metencephalon** - - - - **Cerebellum** - - - - - **Mesencephalon** - - - **Differentiation of the prosencephalon or fore-brain:** - **Deincephalon** - - - - **Telencephalon** - - - - **Nervous System** - - - - - - **Ventricular System of the Brain and Cerebrospinal Fluid (CSF) Circulation** **Ventricles:** Four interconnected cavities (lateral ventricles, third ventricle, fourth ventricle). **CSF Production:** Produced in the choroid plexus within each ventricle, providing cushioning and nourishment for the brain and spinal cord. **Circulation Pathway:** Flows from the lateral ventricles → third ventricle → cerebral aqueduct → fourth ventricle, then enters the subarachnoid space. **Molecular Aspects of Brain Development** **Genes and Signals:** Specific genes and molecular signals, such as Sonic Hedgehog (Shh) and Wnt proteins, are crucial in guiding brain development. **Neurogenesis and Gliogenesis:** Early brain formation involves neurogenesis (formation of neurons) and gliogenesis (formation of glial cells), with cells differentiating based on precise molecular cues. **Brain Anomalies** **Types of Anomalies:** Defects such as anencephaly, hydrocephalus, and holoprosencephaly can occur due to genetic mutations or environmental factors. **Causes:** Common causes include genetic defects, infections, or exposure to teratogens during critical stages of brain development. **Brain Stem and Spinal Cord** **Brain Stem Components:** Includes the midbrain, pons, and medulla oblongata; crucial for basic life functions (e.g., respiration, heart rate). **Spinal Cord:** Connects the brain with the peripheral nervous system, facilitating motor and sensory information relay. **Cranial Nerves** **12 Cranial Nerves:** These nerves emerge directly from the brain and control functions ranging from smell (olfactory nerve) to eye movement (oculomotor nerve) and facial sensation (trigeminal nerve). **Functions:** Each nerve has distinct sensory, motor, or mixed functions essential for bodily functions and responses. **Peripheral Nervous System** **Components:** Consists of nerves outside the brain and spinal cord, including spinal and cranial nerves. **Function:** Transmits signals between the central nervous system and the rest of the body, playing a key role in voluntary and involuntary actions. **Autonomic Nervous System (ANS)** **Divisions:** Comprises sympathetic (fight or flight) and parasympathetic (rest and digest) systems. **Functions:** Regulates involuntary actions like heart rate, blood pressure, and digestion. Works through autonomic ganglia and specialized nerve fibers. **Enteric Nervous System (ENS)** **Structure:** A vast network of neurons lining the gastrointestinal tract, also known as the **\"second brain.\"** **Functions:** Controls gut motility, secretion, and blood flow independently of the CNS, with close interaction with the ANS. **Meninges** **Layers:** Three protective membranes---dura mater, arachnoid mater, and pia mater---surrounding the brain and spinal cord. **Function:** Protects the CNS from trauma, helps circulate CSF, and acts as a barrier against infections.