GI Development Notes - Goebel 2024-2025 PDF

Page 1 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. DEVELOPMENT OF THE DIGESTIVE SYSTEM LECTURE OBJECTIVES 1. Review development of the primordial gut (gut tube). Describe the three divisions of the p...

Page 1 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. DEVELOPMENT OF THE DIGESTIVE SYSTEM LECTURE OBJECTIVES 1. Review development of the primordial gut (gut tube). Describe the three divisions of the primordial gut. List the derivatives for each of the divisions of the gut tube, including blood supply. 2. Describe the molecular regulation involve in the differentiation of the gut tube. Describe the molecular interaction (retinoic acid gradient, regional transcription factors and the role of sonic hedgehog) between the mesoderm and the endoderm that occurs to promote regional differentiation of the gut tube. Describe the germ-layer contributions to the gastro-intestinal tract. 3. Describe the formation of the dorsal and ventral mesenteries and their derivatives Define their mesodermal origin Anatomically define a mesentery Define the peritoneal cavity and its two subdivisions Define intraperitoneal and retroperitoneal Define the regional subdivisions of the dorsal mesentery Describe the ventral mesentery and its derivatives 4. Describe the region of the foregut and its derivatives Describe the formation of the esophagus and its relationship to the developing respiratory system. Describe the esophagus growth/lengthening, muscular fiber transition and positioning within the forming thorax and abdomen. Describe its relationship to the septum transversum and the formation of the esophageal opening in the thoracic diaphragm. Describe the blood supply to the esophagus from the thorax and from the abdomen and its association with the right and left vagus nerves. 5. Describe the development of the stomach, including derivation, course of development and approximate time frame. Describe the timing and degree of longitudinal and anterior-posterior rotation of the stomach. Describe the formation of the greater and lesser curvatures of the stomach and the associated repositioning of their corresponding mesenteries. Describe the formation of the omental bursa (lesser sac) of the peritoneal cavity. 6. Describe the development of the duodenum Describe the dual origin of the duodenum from the primordial gut tube and their boundaries. Describe the dual source of blood supply to the duodenum. Describe the origin of the hepatic diverticulum 7. Describe the formation of the hepatic diverticulum and its role in forming the gallbladder, bile duct, the cystic duct and the hepatic ducts. Describe the origin of the hepatic diverticulum. Describe the molecular signaling source the gives rise to the formation of the hepatic diverticulum. Describe the formation and timing of the gallbladder, bile duct, cystic duct and hepatic ducts. Describe the blood supply source to these structures.  Page 2 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. 8. Describe the formation of the liver Describe the formation of the liver bud and its association with the septum transversum. Describe the source for the hepatocytes and their role in forming the liver sinusoids and biliary ducts. Describe the source of the hematopoietic cells in the developing liver and their role (and timing) for hematopoiesis in the developing fetus. Describe the compartmentation of the ventral mesogastrium by the liver and the resulting formation of the falciform ligament and the lesser omentum. Describe the formation of the bare area of the diaphragm and the liver, and the formation of the coronary ligaments. Describe the source of blood supply to the liver. 9. Describe the formation of the pancreas Describe the origin and initial positioning of the ventral and dorsal pancreatic buds their derivatives and their associations with the dorsal and ventral mesogastrium. Describe the rotation of the ventral pancreas in relation to the dorsal pancreas. Describe the origin and relationship of the bile duct and the main pancreatic duct, and their position before and after the rotations of the duodenum and the ventral pancreas. Describe the relationship of the merging dorsal and ventral pancreas to the superior mesenteric artery and vein. Describe how the developing pancreas and adjoining duodenum are rotated and become mostly retroperitoneal structures. Describe the origin of the pancreatic acini and islet cells and their function. 10. Describe the development of the spleen Describe the germ layer source, blood supply and its positioning within the dorsal mesogastrium. Describe the spleens repositioning to the left side of the abdominal cavity. Describe how the spleen remains intraperitoneal and how it partitions the dorsal mesogastrium into the lienorenal and the gastrosplenic ligaments. 11. Describe the development of the midgut List the derivatives and blood supply source of the structures formed from the midgut. Describe the formation of the primary intestinal loop, its association with the superior mesenteric artery and the vitelline duct. Describe the cause and timing for the rotation of the primary intestinal loop and how the caudal limb is repositioned superior to the ventral limb. Describe the communication of the vitelline duct to the yolk sac and their positioning within the extraembryonic cavity. Describe the role that the extraembryonic cavity plays during the process of physiological herniation. Describe the timing and the order of retraction of the small intestine and cecum from the extraembryonic cavity and their repositioning within the abdominal cavity. Describe the initial position of the cecum in the abdominal cavity upon re-entry and timing of the formation of the appendix. Describe the repositioning and derivatives of the mesentery proper. Describe the repositioning of the cecum and the ascending colon to the right posterior abdominal wall and how the ascending colon becomes a retroperitoneal structure. Describe the formation of the transverse colon from the midgut and the hindgut and its positioning as a intraperitoneal structure. Describe the significance of the hepatic and splenic flexures of the transverse colon.  Page 3 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. 12. Describe the development of the hindgut Describe the derivatives formed from the hindgut and their primary blood supply. Describe the repositioning and fate of their dorsal mesenteries of the distal 1/3rd of the transverse colon, the descending colon, sigmoid colon and the rectum. Describe the association of the urorectal septum with the rectum and the anal canal. Define the region of the cloaca and its relationship with the allantois and the distal end of the foregut and the cloacal membrane. Describe the compartmentalization of the cloaca by the urorecctal septum and the significance of the perineal body. Describe the opening of the urogenital and anal membranes. 13. Describe the development of the anal canal Describe the origin of the upper 2/3’s and lower 1/3 of the anal canal, their blood supply Define the proctodeum and the formation of the anal pit and its contribution to the anal membrane. Define the pectinate line and its significance to the boundaries formed by it with respect to the anal canals formation regional blood supply and sensory innervation. 14. Clinical Relevance Describe the significance of recanalization of the gut tube and how it relates to atresia. Define the reasoning for the formation of an omphalocele and its likely contents. Define gastroschisis and how it differs from an omphalocele. Describe and define the formation of a Meckel’s diverticulum, apply the “rule of 2’s” for its location and its potential to form an umbilical/vitelline fistula. Describe the significance of the formation of an annular pancreas. Describe the reasoning and outcomes of incomplete or errant gut rotations of the primary intestinal loop.  Page 4 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. Lecture Content Outline I. Formation of the primordial gut A. Defining the primordial gut 1. Defining the oropharyngeal and cloacal membranes B. Divisions of the primordial gut 1. Foregut a. Derivatives formed in the thorax b. Derivatives formed in the abdomen c. Source of blood supply 2. Midgut and its derivatives a. Source of blood supply 3. Hindgut and its derivatives a. Source of blood supply II. Molecular regulation of the gut tube A. Molecular regulation controls the development and differentiation of the alimentary tract 1. Role of local mesodermal release of retinoic acid (RA). a. Significance of an RA gradient in signaling regional specific transcription factors. b. Stabilization of regional specific transcription factors rely on reciprocal interactions between by the endoderm and mesoderm. i. Endoderm release of sonic hedgehog (SHH) expression of nested HOX genes by neighboring mesoderm. ii. Regional differential expression of Hox genes commits the region of the gut tube to differentiate into specific organs. B. Germ layer contributions to the gastro-intestinal (alimentary tract) 1. Endoderm: Endothelium and glands 2. Mesoderm: a. Splanchnic mesoderm- b. Somatic mesoderm- c. Neuro crest cells III. Formation of the mesenteries A. The dorsal mesentery-splanchnic mesoderm 1. Attachment-dorsal aorta 2. Contents within dorsal mesentery 3. Regionally defined by week 5 of development a. Dorsal mesogastrium- b. Dorsal mesoduodenum c. Mesentery proper d. Dorsal mesocolon B. The ventral mesentery- derived by the septum transversum 1. Extent of attachment to the anterior body wall 2. Contents and subdivisions a. Lesser omentum b. Falciform ligament c. Coronary and triangular ligaments of the liver C. The parietal peritoneum - derived from somatic mesoderm 1. Defining intraperitoneal and retroperitoneal structures  Page 5 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. IV. Development of the alimentary tract: Foregut A. Overview: 1. Supplied by the celiac artery. B. Development of the esophagus C. Timing of the development and rotation of the stomach D. Development of the duodenum, gallbladder and liver 1. Development of the proximal half of the duodenum 2. Development and formation of the hepatic diverticulum a. Derivatives of the hepatic diverticulum b. Timing of the formation and rotational repositioning of the bile duct system and gallbladder. E. Development of the liver from the endoderm of the foregut and the right septum transversum 1. Origin of liver hepatocytes and formation of liver hepatocytes and biliary ducts. 2. Origin of Hematopoietic and Kupffer cells 3. Growth of the developing liver subdividing the ventral mesogastrium i. Formation of the falciform ligament ii. Formation of the lesser omentum iii. Formation of the coronary and triangular ligaments and creation of the bare areas of the liver & diaphragm. F. Development of the pancreas 1. Formation of the ventral and dorsal pancreatic buds a. Derivatives of the ventral pancreatic bud 2. Formation od the dorsal pancreatic bud a. Derivatives of the dorsal pancreatic bud 3. Reposition of the dorsal and ventral pancreatic buds resulting from the rotations of the stomach and duodenum. 4. Rotation of the gut results in parts of the duodenum and pancreas to become retroperitoneal. 5. Development of the parenchyma into pancreatic acini and islet cell clusters. E. Origin, development and anatomical positioning of the Spleen V. Development of the alimentary tract from the midgut A. Overview: 1. All midgut structures are supplied by the superior mesenteric artery. B. Formation of the primary intestinal loop and vitelline duct 1. Association of the primary intestinal loop with the superior mesenteric artery and vitelline duct. 2. Timing and factors influencing the clockwise rotation of the primary intestinal loop. 3. Contents and relationship of the extraembryonic cavity with the forming peritoneal cavity. a. Defining the extraembryonic cavity b. Relationship of the extraembryonic cavity with the forming peritoneal cavity 1. Role of the extraembryonic cavity in accommodating the process of physiological herniation. 2. Timing and order of retraction of the herniated intestinal loop back into the peritoneal cavity. C. Mesenteries of the intestinal loop 1. Defining the mesentery proper a. Primary intestinal loop retraction and the forming of “the mesentery” b. Repositioning and the fate of the dorsal mesentery of the ascending, and descending colon following full gut rotation. d. Repositioning the transverse mesocolon e. Repositioning of the cecum and the appendix  Page 6 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. V. Development of the hindgut A. Overview: Derivatives, of the alimentary tract, blood supply by the inferior mesenteric A. B. Development of the distal 1/3 of the transverse colon, sigmoid colon and rectum C. Defining the cloaca its relationship with the hindgut and allantois and the forming anorectal septum, and the role of the cloacal membrane forming the urogenital and anal membrane. D. Describe the development of the anal canal 1. Contribution: Upper 2/3’s from the hindgut, distal 1/3 derived from the proctoderm (Ectoderm). Anatomical division is defined by the pectinate line. VI. Clinical Relevance: A. Atresia of the alimentary tract B. Congenital omphalocele: C. Gastroschisis D. Meckel’s diverticulum, with or without Vitelline cysts or vitelline fistula E. Pancreatic abnormalities 1. Accessory pancreatic tissue 2. Annular pancreas F. Errant rotations of the gut 1. Nonrotation 2. Mixed rotation 3. Fixed rotation 4. Incomplete rotation (subphrenic cecum & appendix) 5. Internal hernia 6. Midgut volvulus  Page 7 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. DEVELOPMENT OF THE DIGESTIVE SYSTEM I. FORMATION OF THE PRIMODIAL GUT A. The primordial gut (also called the gut tube) begins to form during the 3rd week of development, and by the end of the 4th week, it is subdivided into a foregut, midgut and hindgut (see Figure 1). Details describing the formation of the gut tube were presented in (Section I) of my notes on the Development of the Respiratory System. Figure 1: Sadler Fig. 7.2: A. 17 days, B. 22 days, C. 24 days 1. The primordial gut is initially closed at its cranial end by the oropharyngeal membrane and at the caudal end by the cloacal membrane. B. Divisions of the primordial gut 1. Foregut a. In the developing thorax, the primordial gut tube gives rise to the pharynx, larynx, trachea and lungs and the esophagus. b. In the developing abdominal cavity, the foregut gives rise to stomach, the proximal half of the duodenum (up to the entrance of the bile duct), the liver, gallbladder, bile & hepatic duct system, the pancreas and the spleen.  Page 8 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. c. This region of the foregut, is mostly supplied by the celiac artery (see Figures 2 & 3). 2. Midgut gives rise to the distal half of the duodenum (from the entrance of the bile duct to the duodenum of the small intestine), the jejunum, ileum, cecum & appendix, ascending colon and the proximal 2/3’s of the transverse colon. a. The midgut is supplied by the superior mesenteric artery (see Figures 2 & 3). 3. Hindgut gives rise to the distal 1/3rd of the transverse colon, descending colon, sigmoid colon, and the rectum up to the pectinate line. It also gives rise to the urinary bladder and urethra (these will be covered in a separate presentation). a. The hindgut is supplied mostly by the inferior mesenteric artery (see Figures 2 & 3). Figure 2: Sadler 15.4 Figure 3: Gray’s Ana. 4.111 II. MOLECULAR REGULATION OF THE GUT TUBE A. The gastrointestinal system (also known as the alimentary tract) differentiates from the primordial gut tube between weeks 4-12. 1. Molecular signaling for the differentiation of the primitive gut tube: Regional differentiation of the gut tube is determined by a local concentration gradient of retinoic acid (RA) being released by the adjacent splanchnic mesoderm.  Page 9 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. a. The concentration of RA is lowest in the developing pharynx, and steadily increases to the distal hind gut. i. The RA gradient initiates regional expression of specific transcription factors (See Figure 4 on the next page) by the endoderm. a. The formation of the esophagus and stomach is dependent upon RA- induced expression of the transcription factor SOX. b. The duodenum is dependent upon the expression of PDX1. c. The small intestine (jejunum and ileum) is dependent upon the expression of CDXC. d. Large intestine and rectum is dependent upon the expression of CDXA. b. The initial patterning by the transcription factors is then stabilized by reciprocal interactions between the endoderm and the splanchnic mesoderm adjacent to the gut tube. i. The endoderm of the gut tube enhances this stabilization process by releasing sonic hedgehog (SHH), which then establishes regional expression of nested HOX genes by the neighboring mesoderm (See Figure 4). ii. The regional differential expression of the HOX genes by the mesoderm commits that region of the gut tube to differentiate into the specific organ, e.g. esophagus, stomach, the small intestine (duodenum, jejunum, ileum), large intestine and cloaca. Figure 4: Sadler Fig. 15.2  Page 10 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. B. Germ layer contributions to the gastro-intestinal tract: 1. Endoderm: gives rise to the epithelium and glands of the GI-tract. 2. Mesoderm: a. Splanchnic mesoderm: gives rise to the lamina propria, muscularis mucosae (Smooth muscle layers), submucosal connective tissue, blood vessels & lymphatics and the adventitia (visceral peritoneum). b. Somatic mesoderm: gives rise to the musculature and skeletal components of the body wall (it has nothing to do with the development of the gut) and lines the abdominal and pelvic cavities with the parietal peritoneum. 3. Neural crest cells: Theses cells give rise to the formation of a submucosal and myenteric nervous plexus (parasympathetic), and the sympathetic autonomic ganglia associated with the aorta (e.g., Celiac, Superior mesenteric, Inferior mesenteric, Renal, Aorticorenal), which are responsible for regulating local glandular secretions and smooth muscle motility throughout the GI-tract. III. FORMATION OF THE MESENTERIES A. The dorsal mesentery: By the 4th week, the primordial gut, inferior to the forming thoracic diaphragm, is suspended at midline, off of the dorsal body wall of the abdomen, by a thin double layered mesothelium that is derived from the splanchnic mesoderm. 1. The dorsal aorta is positioned at the base of the dorsal mesentery. 2. Between the two sheets of the dorsal mesentery blood vessels, lymphatics, connective tissues, and autonomic input (sympathetic, parasympathetic and visceral pain fibers) make their way to and from the GI-tract to the dorsal body wall (See Figure 2 on page 8). a. Note, at this time the entire alimentary tract, from the stomach to the rectum, is suspended off of the body wall, within the developing peritoneal cavity. 3. At 5 weeks, the dorsal mesentery is regionally defined as follows. a. Dorsal mesogastrium: Suspends the developing stomach off of the dorsal body wall. i. The dorsal mesogastrium contains the celiac artery and will give rise to the greater omentum, gastrosplenic and splenorenal ligaments (Figure 5 on the  Page 11 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. next page). These will be described later in these notes, and in detail in Gross Anatomy. ii. It contains the developing spleen. b. Dorsal mesoduodenum: Suspends the region of the duodenum off of the dorsal body wall. i. The dorsal mesoduodenum contains the developing dorsal bud of the pancreas (See Figure 5). c. The mesentery proper: Contains the superior mesenteric artery and suspends the developing jejunum and ileum (small intestines), the cecum, ascending colon and 2/3’s of the transverse colon off of the body wall (See Figure 2 on page 8). Figure 5: Sadler 15.11 d. Dorsal mesocolon: Suspends the developing distal 1/3 of the transverse colon, the sigmoid colon and rectum off of the dorsal body wall and contains the inferior mesenteric artery (See Figure 2 on page 8). B. The ventral mesentery: Is a double layered mesothelium that is derived from the septum transversum of the developing thoracic diaphragm. 1. Unlike the dorsal mesentery, which runs the length of the peritoneal cavity, the ventral mesentery is much shorter in length, and suspends the terminal part of the developing esophagus, the stomach and proximal half of the duodenum (just distal to the bile duct’s entrance into the duodenum). Note that the ventral mesentary’s attachment to the anterior body wall extends from the diaphragm to the umbilicus (See Figure 2 on page 8).  Page 12 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. 2. Structures contained by the ventral mesentery: The ventral mesentery contains the developing liver, gallbladder, the cystic- and hepatic-ducts, the bile duct, the ventral pancreatic bud, and the umbilical vein (will form ligamentum teres/ round ligament, in the adult). 3. Subdivisions of the ventral mesentery: a. The lesser omentum is formed from the portion of the ventral mesentery that resides between the liver and the stomach (See Figure 5). i. The lesser omentum forms the hepatic duodenal ligament and the gastrohepatic ligament). b. The falciform ligament (is formed from the portion of the ventral mesentery that resides between the ventral surface of the liver and the anterior abdominal wall (See Figure 5 on previous page). c. The coronary and triangular ligaments of the liver suspend the liver off of the inferior surface of the thoracic diaphragm. C. The peritoneal cavity: The peritoneal cavity is lined by parietal peritoneum (derived from somatic mesoderm). 1. Defining intraperitoneal and retroperitoneal structures a. Any structure being suspended off of the abdominal or pelvic wall by a mesentery or ligament is described as being an intraperitoneal (or “peritoneal”) structure. b. Any structure that has one surface directly associated with the abdominal or pelvic wall, and the other surface covered by a layer of visceral peritoneum is defined as being a retroperitoneal structure. IV. DEVELOPMENT OF THE ALIMENTARY TRACT: FROM THE FOREGUT A. Overview: The foregut gives rise to the esophagus, stomach and the proximal half of the duodenum (from the stomach up to the entrance of the bile and pancreatic duct). It also is responsible for the formation of the liver, gallbladder and its associated ducts, the pancreas and a major lymphatic organ, the spleen. 1. With the exception of the esophagus, and distal half of the duodenum, all of the structures listed above get their direct blood supply from a branch of the celiac artery.  Page 13 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. B. Development of the Esophagus: See my note on the development of the respiratory system, for details on the differentiation of the pharynx, larynx/respiratory system and the separation of the alimentary and respiratory tracts in this region. 1. Recall that the proximal part of the esophagus resides in the distal pharynx and is positioned dorsal to the developing respiratory tract. 2. During early development, the esophagus is suspended off of the posterior body wall by a mesentery. a. With the growth of the lungs and heart and their corresponding cavities (pleural and pericardial cavities), the esophagus is pushed back against the posterior thoracic wall and invested by connective tissues provided by the splanchnic mesoderm. i. This forms the posterior mediastinum and will contain the majority of the esophagus, the trachea, the rt & left vagal and phrenic nerves, and the roots of the lungs. 3. The esophagus elongates with the growth of the lungs and the heart, along with the lengthening of both the pleural and pericardial cavities. 4. Splanchnic mesoderm gives rise to the muscular coat of the esophagus. a. The upper 2/3’s of the esophagus contains striated muscle bundles, which are innervated by the Vagus N. b. The distal 1/3 of the esophagus transitions into smooth muscle fibers and receives its innervation from the splanchnic plexus (e.g., autonomic nervous system, provided by parasympathetic (Vagus N.) and sympathetic drive). 5. At the 4th month of development, the distal end of the esophagus is encroached by the pleuroperitoneal folds and the septum transversum of the developing thoracic diaphragm. This creates the esophageal opening in the adult thoracic diaphragm. a. Note that a short distal segment of the esophagus passes through the esophageal opening of the diaphragm and is located within the abdominal portion of the peritoneal cavity. 6. Blood supply to the esophagus. a. In the thorax: is provided by 2-3 esophageal branches coming off of the dorsal aorta.  Page 14 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. b. In the abdomen the distal part of the esophagus receives its blood supply from a branch of the celiac artery (e.g., left gastric A). C. Development and rotations of the stomach: 1. During the 3rd week of development, the distal part of the foregut gives rise to the stomach. a. At this stage, the stomach is a linear tube that is suspended off of the posterior abdominal wall (at midline) by the dorsal mesogastrium, and ventrally, by the ventral mesogastrium (See Figure 6 on the next page). b. Also note that the primordial stomach is flanked by the right and left vagal trunks. Figure 6: Sadler Fig 14.1 2. At 28 days, the stomach grows into a fusiform shaped structure (See Figure 7 on the next page), and begins to rotate 90 degrees clockwise about its longitudinal axis (from a cranial view). See Figure 7A. a. Note that the distal half of the esophagus, and the proximal part of the duodenum, also rotates with the stomach. b. Through this rotation, the left side of the developing stomach (from stage 3 weeks) becomes the ventral surface of the stomach, while the right side becomes its dorsal surface.  Page 15 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. c. This rotation is completed around day 40 (See Figure 7C). 3. Following the rotation of the stomach, the left side (formally the dorsal side before rotation) grows and elongates at a faster rate than the rotated right side, to give rise to the greater curvature of the stomach. The slower growing right side (formally the ventral surface prior to rotation) gives rise to the lesser curvature of the stomach (See Figure 7 C-E). a. The accompanying left and right vagal trunks (not illustrated in Figure 7) follow their associated surfaces on the stomach, such that the left vagal trunk provides innervation to the ventral surface of the stomach, and the right vagal trunk provides innervation to the dorsal surface. Figure 7: Sadler Fig. 15.8 b. Note that the greater curvature of the stomach is initially positioned to the left side, and the slower growing ventral border (which becomes the lesser curvature of the stomach) is positioned to the right side at day 40 (See Figure 7D). 5. During the 6th week, the continued accelerated growth of the greater curvature of the stomach promotes a clockwise rotation ~55-60° about its anterio-posterior axis (See  Page 16 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. Figure 7D). This causes the distal end of the stomach (called the pylorus) to move upward and to the right, and the proximal part of the stomach (called the cardiac portion) to be displaced slightly downward and to the left (See Figure 7D and E on the previous page) to finalize the positioning of the stomach. 6. The primary source of the arterial supply to the stomach and the proximal half of the duodenum are supplied by branches coming from the celiac artery. 7. The disproportionate growth of the stomach and its rotation about its longitudinal axis alters the positioning of the dorsal mesogastrium and ventral mesogastrium. a. This rotation pulls the dorsal mesogastrium to the left and creates a space between the dorsal surface of the stomach and the dorsal mesogastrium. This space will contribute to the formation of the omental bursa (also known as the lesser sac of the peritoneal cavity; See Figure 5 on page 12). i. The portion of the dorsal mesogastrium that comes in contact with the parietal peritoneum of the body wall will fuse together. a. Following fusion of the dorsal mesogastrium with the parietal peritoneum, the posterior sheet of the dorsal mesogastrium and the underlying parietal peritoneum degenerates, leaving only the anterior sheet of the dorsal mesogastrium covering the posterior abnormal wall. b. The rotations of the developing stomach will also displace the ventral mesogastrium to the right (See Figure 8 and Figure 5 on page 12). Differentiation of the ventral mesogastrium will be described later in these notes. Figure 8: Sadler 15.12  Page 17 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. D. Development of the duodenum, gallbladder, liver, pancreas and the spleen. 1. The duodenum is derived from the terminal end of the foregut and from the proximal end of the midgut, with the border between the two, located just inferior to the combined entrance of the bile/pancreatic ducts (described below). a. Because of the dual origin of the duodenum, its proximal half receives blood supply from the celiac artery, while its distal half is supplied by the superior mesenteric artery. b. The duodenum and its dorsal and ventral mesenteries are re-positioning into a C- shaped structure that becomes associated mostly with the posterior abdominal wall (i.e. becomes mostly retroperitoneal). Note, this results from the combined rotations of the stomach, and by the primary intestinal loop (discussed later in these notes: Section V.B.). E. Development of the hepatic diverticulum and its role in forming the Gallbladder, Bile duct system, Liver and Pancreas. 1. Mesodermal induction of the hepatic diverticulum: During the third week of development, an outgrowth of endoderm called the hepatic diverticulum (or liver bud) forms, in a region that will become mid-duodenum (See Figure 9). a. The hepatic diverticulum (endoderm in origin) is initially induced by local release of fibroblast growth factors (FGF2) from the neighboring cardiac mesoderm around day 16-17. Figure 9: Moore b. By day 30, the hepatic diverticulum has given rise to the liver bud, the hepatic/bile duct system, the gallbladder & cystic duct, the bile duct, as well as giving rise to the ventral pancreatic bud (See Figure 10A).  Page 18 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. Day 30 Day 35 Figure 10: Sadler 15.19 2. Formation of the bile duct & gallbladder: a. At around day 25, the hepatic diverticulum has formed an endoderm epithelial lined duct that arises from the right side of the developing duodenum (before rotation of the stomach). See Figure 10A. b. The hepatic diverticulum extends into the right septum transversum (derived from splanchnic mesoderm and also gives rise to part of the thoracic diaphragm), where the rapidly proliferating epithelial cells (endoderm), form the liver (hepatic) bud (See Figure 10A). c. In addition, between the liver bud and the duodenum, the hepatic diverticulum will also form the duct system that will give rise to the gallbladder & cystic duct, the hepatic duct system, and the (common) bile duct (see Figure 10B). d. At 5 weeks, the stomach’s clockwise longitudinal rotation causes the developing duodenum to rotate with it (Figure 11A &B). i. This causes the bile duct (and the ventral pancreas and its duct, discussed below) to rotate to the inferior left side of the duodenum by the 6th week (Figure 11A & B). ii. Also during this time, the right and left hepatic ducts and developing branches form within the developing liver parenchyma. Figure 11: Sadler 15.20  Page 19 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. 3. Formation of the liver: The induction of the hepatic diverticulum allows the endoderm of the foregut region (in the region of the future mid-duodenum), to promote proliferation of the liver hepatocytes within the right septum transversum (mesenchyme derived), as described above. a. The rapidly proliferating hepatocytes give rise to the majority of the liver parenchyma. These cells form liver epithelial cords that intermingle with vitelline and umbilical veins, to form the hepatic sinusoids. Likewise, biliary ducts (also derived from endoderm) will form between adjoining hepatocytes to facilitate the drainage of bile from the liver to the duodenum. b. Hematopoietic cells, Kupffer cells and connective tissues in the liver are derived from the septum transversum (mesoderm). i. Important for the growth and development of the fetus is the invasion of the hemoatopetic cells into the liver parenchyma. These cells form nested hematopoietic islands, which in turn, ramps up production of red and white blood cells in the developing fetus up to the seventh month of development. c. The rapid growth of the liver causes it to “bulge” inferiorly into the abdominal cavity from the septum transversum, within the confines of the ventral mesogastrium. i. At this juncture, the ventral mesogastrium is subdivided into two regions. a. The portion of the ventral mesogastrium that resides between the anterior abdominal wall and the ventral surface of the developing liver is defined as the falciform ligament (See Figure 12B). b. The portion of the ventral mesogastrium that resides between the liver and lesser curvature of the developing stomach is defined as the lesser omentum (See Figure 12B). ~ 40 days ~ 36 days Figure 12: Sadler 15.15  Page 20 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. d. Because the liver develops within the septum transversum (See Figure 12A), its superior surface (called the diaphragmatic surface of the liver) and the corresponding inferior surface of the diaphragm are bare (i.e. not covered by peritoneum (See Sadler Figure 12B). i. Mesoderm (from the septum transversum) forms the visceral peritoneal covering of the anterior, posterior and inferior visceral surfaces of the developing liver and suspends it to the inferior surface of the developing thoracic diaphragm by the anterior and posterior coronary ligaments (You will see these in the Gross Anatomy Lab). 4. Formation of the pancreas: Beginning around day 30, the pancreas begins to form from two endodermal out-pockets (the ventral- and dorsal-pancreatic buds) arising from mid-duodenum. These buds will develop into a dorsal and ventral pancreas respectively (See Figure 10 on page 19 on these notes). a. The ventral pancreatic bud is associated with the proximal region of the hepatic diverticulum (See Figure 10 on page 19 of these notes). i. The ventral pancreas develops within the confines of the ventral mesoduodenum. ii. The ventral pancreas will give rise to the main pancreatic duct, the uncinate process, and the dorsal half of the head of the pancreas (See Figure 13 on the next page). b. The dorsal pancreatic bud will give rise to the ventral portion of the pancreas and is associated with the posterior longitudinal axis of the duodenum, directly opposed to the ventral pancreatic bud, and develops within the dorsal mesoduodenum (See Figure 11 on page 20 of these notes). i. The dorsal pancreas will give rise to the ventral-half of the head, the neck, body and tail of the pancreas and the accessory pancreatic duct (See Figure 13 on the next page). c. Repositioning of the ventral and dorsal pancreatic buds is dependent upon the rotation of the stomach and duodenum: With the rotation of the stomach and duodenum occurring between weeks 5-6, the ventral pancreas rotates to lie posterior to the developing dorsal pancreas (See Figure 11A on page 20 of my notes). i. With further rotation of the intestines (discussed below), the duodenum becomes “C-shaped” and the two developing pancreatic buds merge medial to the duodenum (See Figure 13 on the next page).  Page 21 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. ii. With this rotation, the entrance of the bile duct and the main pancreatic duct to the duodenum are now positioned on the medial surface of the descending portion of the duodenum (see Figure11B, on page 20 of these notes). a. Upon the merging of the two pancreatic buds, the dorsal pancreatic duct is signaled to merge with the main pancreatic duct of the ventral pancreas. As a result of this merger, the accessory pancreatic duct (emptying the dorsal pancreas into the duodenum prior to merging), usually degenerates. However, according to a number of sources, the accessory pancreatic duct remains functional in ~10% of the population (see Figure 14). Look for this in your cadaver. Figure 13: Netter 281A Figure 14: Netter  Page 22 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. iii. It should be noted here, that the superior mesenteric artery and the superior mesenteric vein are encircled by the merging of the dorsal and ventral pancreas. This results in the head of the pancreas to be positioned to the right, the body anterior, and the uncinate process inferior to the superior mesenteric artery and vein (See Figure 13 on previous page). d. Repositioning of the developing pancreas to the posterior abdominal wall: The rapid growth of the overlying colon and the rotation of the intestinal loop (discussed below) cause the distal half of the duodenum and all but the tail of the pancreas to be pressed up against the posterior abdominal wall. Their respective visceral peritoneum coverings that are in contact with the parietal peritoneum of the posterior wall fuse together, and are later reabsorbed. Thus, the majority the pancreas (except for the tail region which remains peritoneal), and duodenum (except for the 1st and 4th parts which also remain peritoneal) are regionally described as being retroperitoneal. See Figure 13 on previous page. e. Exocrine and endocrine function: During the third month, the parenchyma of the pancreas segregates into forming pancreatic acini (glandular secretory cells) and clusters of islet cells, which reside in between the acini. i. The pancreatic acini cells release enzymes into the duodenum that facilitate the breakdown of fats/lipids. ii. The islet cells (of Langerhans) differentiate into alpha cells and beta cells. a. Alpha cells release glucagon, which stimulates the breakdown of glycogen in the hepatocytes and the release of glucose into the circulatory system to regulate/maintain glucose levels. b. Beta cells release insulin into the circulatory system, which promotes the uptake of glucose by the hepatocytes and the synthesis and storage of glycogen within these cells. F. Development and positioning of the Spleen: The spleen is a vascular lymphatic organ that is not related to the digestive system. 1. Development of the spleen occurs during the fifth week and is derived from a mass of mesenchymal cells located between the two mesothelial layers of the dorsal mesogastrium (See Figure 5A &B on page 12 of my notes) and receives its blood supply from a branch of the celiac artery.  Page 23 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. 2. During the rotation and rapid growth of the greater curvature of the stomach (see above), the spleen, along with the dorsal mesogastrium that contains it, are displaced to the left side of the body (See Sadler Figure 5A & B on page 12 of these notes). 3. The spleen continues to grow within the dorsal mesogastrium and remains an intraperitoneal organ suspended within the abdominal cavity. a. Following the rotations of the stomach, the spleen will be positioned on the left side, posterior-lateral to the stomach. b. The portion of the dorsal mesogastrium, that overlies the developing left kidney located in the posterior abdominal wall and extends to the spleen becomes the splenorenal ligament. c. The portion of the dorsal mesogastrium between the spleen and the stomach becomes the gastrosplenic ligament. See Figure 5 on page 12 of these notes. V. DEVELOPMENT OF THE MIDGUT A. Overview: The midgut gives rise to the distal-half of the duodenum (starting below the entrance of the bile duct) the jejunum and the ileum (small intestines) the cecum, appendix, the ascending colon and 2/3’s of the proximal transverse colon. 1. All of the listed structures receive their blood supply from the branches of the superior mesenteric artery. Innervation is provided by the vagal plexus (parasympathetic) and by the thoracic splanchnic nerves (sympathetic). B. Formation of the primary intestinal loop of the midgut and its rotation. Between the 4th and 5th week, rapid growth of the midgut results in the formation of the primary intestinal loop (See Figure 15 on the next page). 1. The primary intestinal loop is centered about the superior mesenteric artery, the dorsal mesentery off of the posterior abdominal wall (will become “the mesentery”), and the vitelline duct, which extends to the yolk sac located in the extraembryonic cavity of the umbilical cord on the anterior abdominal wall (See Figure 2 on page 8 of my notes and Figure 15on the next page). 2. Between the 5th -8th week of development, rapid growth of the portion of the midgut between the distal half of the duodenum and the vitelline duct (e.g., anterior half of the loop), causes the primary intestinal loop to rotate roughly 180°, counterclockwise, when viewed (ventral to dorsal) about its axis (See Sadler Figures 15A and B and Figure 16 on next page). Note that the cecal bud and the transverse  Page 24 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. colon both pass ventral to the developing duodenum (See Figures 15B below and 16, on the next page). Figure 15: Sadler Fig. 15.25 a. Counterclockwise rotation continues for another 90° (for a total of approximately 270°). This additional rotation results from the accelerated growth of the jejunum and the ileum (forming their intestinal coiled loops), and especially from the region of the distal gut tube that will give rise to the large intestine (See Figure 16D on the next page). Rotation of the primary intestinal loop is completed by week 10.  Page 25 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. Figure 16: Moore 11-13 3. During early development, the midgut remains in direct communication with the yolk sac via the vitelline duct (See Figure 16A-C). a. The yolk sac becomes incorporated in a serous mesothelial lined sac (defined as the extraembryonic cavity) contained within the amnion-covering of the umbilical cord (See Figure 16B).  Page 26 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. Figure 16: Sadler 8.16 b. The extraembryonic cavity remains continuous with the developing peritoneal cavity of the embryo and will accommodate the rapid growth of the small intestines (jejunum and ileum) and cecum during weeks 6-10 of development. i. This normal development process is known as physiological herniation and occurs as a result of the inability of the slow growing abdominal cavity to accommodate the rapidly growing intestines during this period (See Figure 17 on the next page: Fetus stage ~58 days gestation). c. Retraction of the herniated intestinal loop from the extraembryonic cavity begins around the 10th week. i. The proximal part of the jejunum is the first part of the intestine to reenter the abdominal cavity. Its coiled loops are sequentially layered beginning on the left side, inferior to the stomach and spleen, and progressing to the lower right side of the abdominal cavity with increasing folding of the jejunum followed by the ileum.  Page 27 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. Figure 17: Moore 11-14A ii. The cecal bud (which defines the proximal part of the large intestine, (e.g. colon) is the last part of the herniated intestine to reenter the abdominal cavity. a. Upon reentry into the abdominal cavity, the cecal bud (which will give rise to the cecum and the appendix) is initially positioned in the upper right quadrant of the abdominal cavity just inferior to the liver, (see Figure 16, on the previous page). However, with accelerated growth of the colon following re-entry into the abdominal cavity occurring during this period, the cecum and the adjoining ascending colon are displaced inferiorly, along the right posterior abdominal wall, with the cecum ending up resting in the right iliac fossa and the ascending colon becoming retroperitoneal on the right side of the posterior abdominal wall. b. During the descent of the developing cecum, its distal end forms a narrow diverticulum called the appendix (see Figure 16, on page 28). D. Mesenteries of the intestinal loop 1. The mesentery proper: Prior to the rotation of the primary intestinal loop, the superior mesenteric artery, which is invested by the mesentery proper, supplies the caudal half of the duodenum, the developing jejunum, ileum, cecal bud, the developing ascending colon and approximately 2/3’s of the transverse colon (see Figure 2 on page 8 of these notes). a. As the intestinal loop grows and rotates, the portion of the mesentery proper attached to the ascending colon and the transverse colon gets repositioned and  Page 28 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. isolated from the mesentery of the developing ileum and jejunum. The mesentery suspending the ileum and the jejunum is anatomically redefined as “the mesentery”. b. With the 270° counterclockwise rotation of the primary intestinal loop, the caudal limb of the loop containing the cecal bud, ascending colon and the proximal half of the transverse colon moves to the mid-upper right side of the abdominal cavity causing their corresponding dorsal mesenteries to twist around the origin of the superior mesenteric artery (see Moore Figure 16, on page 28 of my notes). c. With the ascending and descending portions of the colon reaching their final anatomical positions, their corresponding dorsal mesenteries press against, and then fuse with, the parietal peritoneum of the posterior abdominal wall (See Figure 18 B & C on the next page). i. After fusion of these layers, the ascending and descending colon are (under normal development conditions) are permanently attached to the posterior abdominal wall (i.e., no longer suspended off of the posterior wall by their dorsal mesenteries) and become retroperitoneal structures (see Figure 18. 11- 15 B & E on the next page). d. The transverse colon drags its dorsal mesentery with it, on a horizontal plane, as it crosses the posterior abdominal wall. i. Its mesentery (now called the transverse mesocolon) remains intact during the rotation process and suspends the transverse colon off of the posterior abdominal wall. Thus, the transverse colon remains intraperitoneal. ii. The transition from the ascending colon (retroperitoneal) to the transverse colon (intraperitoneal) on the right side is called the hepatic flexure of the colon. iii. The transition from the transverse colon (intraperitoneal) to the descending colon (retroperitoneal), on the left side, is called the splenic flexure of the colon. iv. With the horizontal attachment of the transverse mesocolon to the posterior abdominal wall positioned just inferior to the horizontal attachment of the greater omentum of the stomach (derived from the dorsal mesogastrium) the two mesenteries fuse in the region between the posterior abdominal wall and the transverse colon (see Figure 18 C and F on the next page).  Page 29 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. e. Note here that, the lower end of the cecum and the appendix maintain their corresponding mesenteries (i.e. are suspended off of the posterior abdominal wall) and are classified as being intraperitoneal structures. Figure 18: Moore 11-15 VI. DEVELOPMENT OF THE HINDGUT A. Overview: 1. The hindgut gives rise to the distal 1/3rd of the transvers colon, the descending colon, sigmoid colon, rectum and the upper part of the anal canal (above the pectinate line). 2. The endodermal lining of the hindgut also forms the lining of the urinary bladder and the urethra (this will be covered in a separate lecture). 3. Most of the hindgut receives its blood supply from the inferior mesenteric artery (See Figures 2 & 3 on page 8 of these notes).  Page 30 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. B. Development of the transverse colon, descending colon, sigmoid colon and rectum: The growth of the distal 1/3 of the transverse colon, descending, sigmoid colon, and the rectum is derived from the hindgut and is centered-about the inferior mesenteric artery. Its development follows the timing of the growth and differentiation of the alimentary tract derived by the midgut. 1. The distal 1/3rd of the transverse colon, the descending colon and the sigmoid colon are displaced to the left side of the posterior body wall (See Figure 8 on page 17, and Figure 19 on the next page). a. The distal 1/3rd of the transverse colon (in continuation with the 2/3rds of the transverse colon derived from the midgut), remains suspended by its mesentery (now called the transverse mesocolon), and ends at the splenic flexure, where it then transitions into the descending colon. b. The descending colon is displaced laterally by the growth of the small intestines. Like the ascending colon, its dorsal mesentery fuses with the peritoneum of the posterior abdominal wall, thus making the descending colon retroperitoneal. See Figure 18B & E on the previous page. c. The sigmoid colon is displaced to the lower left side of the abdominal cavity; however, it remains suspended by its dorsal mesentery (called the sigmoid mesocolon) and is defined as being intraperitoneal (Figure 19B). d. The rectum is a retroperitoneal structure that is positioned on the pelvic surface of the developing sacrum. During development, most of its anterior surface is in contact with the developing urorectal septum, which provides the connective tissue barrier between it, and the developing urogenital region anterior to it (more on this below). Figure 19: Sadler 15.27  Page 31 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. C. The cloaca and the development of the rectum, anorectal canal, urogenital sinus and the subdivision of the urorectal septum. 1. The cloaca is an enlarged region located at the terminal end of the hindgut. It is subdivided into anterior and posterior parts by a forming mesodermal septum called the urorectal septum (See Figure 20). a. The cloaca ends as a thin double layered epithelium, with the inner surface epithelium derived by the endoderm of the hindgut, and the opposing outer layer of epithelium being supplied by the ectoderm to form the cloacal membrane. b. Early during development, the anterior and posterior parts of the cloaca are in communication with each other, where the allantois (which will give rise to the urinary bladder and urethra) enters the anterior region of the cloaca, and the forming rectum of the hindgut enters the posterior part of the cloaca. Note, at this stage the urorectal septum has not fused to the cloacal membrane (See Figure 20A & B). Thus at this time, the future urogenital tract and the alimentary tracts are in communication with each other. Figure 20: Sadler 15.36 c. Growth and elongation of the urogenital septum causes it to fuse with the cloacal membrane, subdividing the cloaca membrane into an anterior urogenital membrane, and a posterior anal membrane (Figure 20C). i. The portion of the urogenital septum that comes in contact with the cloacal membrane thickens into a fibrous mass and forms the perineal body (see Figure 20).  Page 32 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. d. During the 7th week of development, both the anal membrane and the urogenital membrane rupture, creating the anal opening for the hindgut and the opening to the urogenital sinus respectively. i. During this time, the dorsal mesentery to the rectum is reabsorbed to the posterior abdominal wall resulting in the rectum to become a retroperitoneal structure. ii. Further development of the urogenital system will be described in a separate lecture. D. Development of the Anal Canal 1. The upper 2/3’s of the anal canal is derived from the endoderm of the hindgut. It’s inferior border is defined by the pectinate line (See Figure 21). a. This region is supplied by the right and left superior rectal arteries (branches from the right and left inferior mesenteric arteries) and the right and left middle rectal arteries (branches of the right and left internal iliac arteries). 2. The lower 1/3 of the anal canal is derived from ectoderm originating from a region called the proctodeum. a. The rapid proliferation of the proctodeum creates the anal pit with the apex of the pit forming the ectodermal layer of the anal membrane (See Figure 20 on the previous page). b. This region is supplied by the right and left inferior rectal arteries (branches from the right and left internal pudendal arteries). 3. The pectinate line demarcates the boundary between the upper 2/3’s (endoderm derived: yellow region); and the lower 1/3rd (ectoderm derived: blue region) of the anal canal (Figure 21). Figure 21  Page 33 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. a. Note that sensory above the pectinate line is receptive to pressure and distension but is insensitive to touch and temperature (visceral sensory). Sensation below the pectinate line is receptive to pain, temperature and touch (somatic sensory). VII. Clinical Relevance A. Atresia of the alimentary tract: As was seen in the development of the respiratory system, the rapid growth of the endoderm of the alimentary tract also involves the proliferation of the endoderm within the future lumen of the developing tube. This proliferation fully occludes the lumen (Figure 22A). Recanalization of the lumen is a controlled process that involves apoptosis (programed cell death) of endothelial derived cells occupying the future lumen of the tube. Complete recanalization yields a muscular tube lined by a single layer of columnar epithelium. 1. Failure to undergo recanalization will result in the atresia (e.g. blockage of this region of the digestive tube). This can occur anywhere along the alimentary tract. Figure 22: Sadler 15.18 B. Omphalocele: An omphalocele results from the failure of the small intestines (jejunum and ileum) and in some cases the liver, to return back into the abdominal cavity following the process of physiological herniation. This occurs in 1/5000 births, with 50% of them associated with genetic abnormalities. An omphalocele resides in the extraembryonic cavity, located in the proximal part of the umbilical cord. Note, the herniated contents are contained by the parietal peritoneum and the amnion (Figure 23) and are not subjected to direct contact with the amniotic fluid, (which is corrosive to the exposed viscera. See C below). Post-natal surgical repair will correct this. Figure 23: Moore 11-17A  Page 34 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. C. Gastroschisis: Is a developmental defect that occurs in the anterior abdominal wall away from the umbilical cord (usually on the right side, lateral to the median plane). This results in the abdominal viscera protruding out of the abdominal cavity and into the amniotic cavity. The loops of the bowel are exposed directly to the amniotic fluid, which has a corrosive effect of the exposed alimentary tract. Other risks include the intestinal loops twisting around each other (process called “volvulus) and cut off blood supply. Thus, if not detected in time, that region will become necrotic. The occurrence is 1/2000 births and is more prominent in males than females (See Figure 24). This can be surgically corrected. Figure 24: Moore 11-19A D. Meckel’s diverticulum (ileal diverticulum): Results from the incomplete degeneration of the vitelline duct (which normally occurs around the 7th week of development). In the adult this diverticulum (2-4% occurrence) can be found on the free border of the ileum approximately 40-60 cm (~2 feet) from the ileocolic junction (See Figure 25 on the next page). 1. Normally, this diverticulum doesn’t present any symptoms, however, where the vitelline duct remains patent (called an umbilical or vitelline fistula) over its entire length (from the ileum to the umbilicus), it would allow fecal discharge to reach and accumulate around the umbilicus (See Figure 25C). 2. The wall of the diverticulum may contain small tissue patches of gastric and pancreatic tissues, with gastric tissues sometimes causing ulceration of the endothelial lining. This can cause substantial bleeding into lumen of the diverticulum that can be detected in the fecal stool.  Page 35 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. 3. The rule of two’s: Meckel’s diverticulum is located in the ileum and is usually 2 inches long, is located ~2 feet from the ileocecal junction and occurs in 2% of the population. Look for this in your cadaver!!!!! Figure 25: Sadler 15-32 E. Pancreatic abnormalities: 1. Accessory pancreatic tissue: Accessory pancreatic tissue can randomly appear anywhere along the developing gut tube, including the vitelline duct, and is often detected within Meckel’s diverticulum. Under normal conditions, their presence has no symptomology. 2. Annular pancreas: An annular pancreas is a rare occurrence, where the ventral pancreatic bud becomes bifid (Figure 26A). This results with one part rotating normally (posteriorly to the duodenum) to meet the dorsal pancreatic bud, while the other ventral bud splits off and rotates ventrally to meet the dorsal pancreatic bud (Figure 26B on the next page). This forms a ring of pancreatic tissue around descending duodenum (Figure 26C). Normally, the restriction by the annular pancreas on the duodenum doesn’t present any problems, but does become an issue if the pancreatic tissue becomes inflamed (e.g., when pancreatitis occurs). The swelling Figure 26: Moore 11-11  Page 36 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. of this ring of pancreatic tissue can lead to stenosis of the duodenum, and obstruct the passage of digested food from the stomach and proximal half of the duodenum beyond this region. This can become life-threatening. F. Errant rotation of gut. Many possibilities can occur (See Figure 27). 1. Nonrotation (Figure 27A) of the midgut occurs when the intestine does not rotate when it reenters the abdomen following physiologic herniation. As a result, the caudal limb from the intestinal loop returns first, whereby the large intestine is displaced to the left side followed by the ileum and then the jejunum being displaced to the right side of the abdomen. Figure 27: Moore 11-20 2. Mixed rotation (Figure 27B) of the midgut causes the cecum to become fixed to the upper right posterior abdominal wall by peritoneal bands from the overlaying duodenum. This results in an over-rotation of the mesentery that can result in the strangulation or atresia (narrowing) of this section of intestine. 3. Reverse rotation (Figure 27C on the previous page) is always interesting to see down in the Gross lab (I have seen this once in my 30+ year career here). The only problem that can result from this is that “The Mesentery” containing the superior mesenteric artery and vein passes anterior to the transverse colon  Page 37 of 37 Development of the Digestive System Dennis J. Goebel Sr., Ph.D. (normally it passes inferior to it) and it can result in compressing this part of the transverse colon, causing atresia in this region of the colon. 4. Incomplete rotation (Figure 27D on the previous page, Subhepatic cecum & appendix) results from the failure of the cecal bud and ascending colon to be displaced down the right side of the posterior abdominal wall. This variant is usually asymptomatic. 5. Internal hernia (Figure 27E on the previous page) results when the small intestines “blunt-dissect” there way under the pancreas and the duodenum. Recall that both the pancreas and the duodenum were once intraperitoneal structures prior to the stomach rotations, and that following rotation, they are pushed onto the right posterior abdominal wall, whereby their peritoneal surface fuses with the peritoneal surface of the posterior abdominal wall. This plane of fusion is susceptible to the dissection by the highly motile small intestines, whereby they can dissect their way under the duodenum and pancreas and create a peritoneal lined pouch posterior to them. FYI, this form of herniation is not limited to early development and can occur anytime following birth out to-old age… 6. Midgut volvulus (Figure 27F on the previous page) results from a reverse rotation (See Figure 27C on the previous page) whereby, the cecum, and the ascending colon are prevented from becoming associated with the posterior abdominal wall and will remain intraperitoneal structures (i.e. suspended off of the posterior abdominal wall by their corresponding dorsal mesenteries). Duodenal constriction (atresia) by the motile cecum and ascending colon can occur. This can become chronic and potentially life-threatening and requires emergency surgery.