The early developing gastrointestinal tract
This lecture will cover the early development of the endoderm layer of the trilaminar embryo as it contributes to the lining, glands and organs of the gastrointestinal tract (GIT
). The endoderm contribution to the respiratory system will be covered in a separate lecture
Gastrulation, or gut formation, was historically the easiest observable feature of frog development. In human development, during the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different structures.
The oral cavity (mouth) is formed following breakdown of the buccopharyngeal membrane (= oropharyngeal or oral) and the opening means that it contains amniotic fluid, which is also swallowed later in development.
The large mid-gut is generated by lateral embryonic folding which "pinches off" a pocket of the yolk sac, the 2 compartments continue to communicate through the vitelline duct.
The hindgut (cloaca) will later be divided into separate urogenital and rectal regions that end at the cloacal membrane.
Note that we will be returning in the laboratory and later (head, endocrine, neural crest) to discuss the gastrointestinal tract, associated organs and physical growth changes.
2018 Lecture - Print PDF
| Some Recent Articles
Castillo-Azofeifa D, Seidel K, Gross L, Golden EJ, Jacquez B, Klein OD & Barlow LA. (2018). SOX2 regulation by hedgehog signaling controls adult lingual epithelium homeostasis. Development , 145, . PMID: 29945863 DOI.
- "Adult tongue epithelium is continuously renewed from epithelial progenitor cells, a process that requires hedgehog (HH) signaling. In summary, we show that SOX2 functions downstream of HH signaling to regulate lingual epithelium homeostasis." SOX
Cobourne MT, Iseki S, Birjandi AA, Adel Al-Lami H, Thauvin-Robinet C, Xavier GM & Liu KJ. (2018). How to make a tongue: Cellular and molecular regulation of muscle and connective tissue formation during mammalian tongue development. Semin. Cell Dev. Biol. , , . PMID: 29784581 DOI.
- "Although the gross embryological contributions to tongue formation have been known for many years, it is only relatively recently that the molecular pathways regulating these processes have begun to be discovered. In particular, there is now evidence that the Hedgehog, TGF-beta, WNT and Notch signaling pathways all play an important role in mediating appropriate signaling interactions between the epithelial, cranial neural crest and mesodermal cell populations that are required to form the tongue."
| Midgut Rotation
Carnegie stage 14 (CS14) orientation of the midgut loop and its mesentery during the 5th week follows the helical body axis.
- A - Dorsal view of the reconstruction of a CS14 embryo (s5029). Note the left-sided juxtaposition of the head relative to the caudal end of the body, reflecting the helical body axis. The successive parts of the midgut are shown in a rainbow color gradient (see legend color codes). Note that the vitelline artery (3) and the right vitelline vein (7) traverse the vitelline duct (8) at the apex of the midgut loop. The arrows indicate the changes occurring during straightening of the body axis in CS15 and CS16 embryos.
- B - shows the position of the developing midgut mesentery (10) between both limbs of the midgut. Note the limited craniocaudal extension of the mesentery at this stage (10). The beige area identifies the region where the intestinal mesenchyme is attached to the dorsal body wall.
- C - Histological section of embryo s5029 with right vitelline vein (7), vitelline artery (3), cecum (Ce) and developing dorsal midgut mesentery (10). Due to the helical body axis, the caudal end of the body is cut near transversely (with left (L) and right (R) sides), whereas more cranially, the body is cut almost sagittally (V: ventral; D: dorsal). Note that the midgut mesentery (10) is ~4-fold thinner than the mesenchymal mass surrounding the intestine.
BMC Developmental Biology 2015, 15:31
The later developing gastrointestinal tract
- Understanding of germ layer contributions to the early gastrointestinal tract (GIT)
- Understanding of the folding of the GIT
- Understanding of three main GIT embryonic divisions
- Understanding of associated organ development (liver, pancreas, spleen)
- Brief understanding of mechanical changes (rotations) during GIT development
- Brief understanding of gastrointestinal abnormalities
| Hill, M.A. (2018). UNSW Embryology (18th ed.) Retrieved September 23, 2018, from https://embryology.med.unsw.edu.au
2014 | 2014 PDF
| Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The developing human: clinically oriented embryology (9th ed.). Philadelphia: Saunders.
|| The following chapter links only work with a UNSW connection.
| Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. & Francis-West, P.H. (2009). Larsen's human embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
|| The following chapter links only work with a UNSW connection.
Chapter 14 Development of the Gastrointestinal Tract
Germ Layer Contributions
- endoderm - epithelium and associated glands.
- mesoderm (splanchnic) - mesentry, connective tissues, smooth muscle, blood vessels.
- ectoderm (neural crest) - enteric nervous system.
Both endoderm and mesoderm will also have major contributions to associated organs.
Folding of the embryonic disc occurs ventrally around the notochord, which forms a rod-like region running rostro-caudally in the midline.
In relation to the notochord:
- Laterally (either side of the notochord) lies mesoderm.
- Rostrally (above the notochord end) lies the buccopharyngeal membrane, above this again is the mesoderm region forming the heart.
- Caudally (below the notochord end) lies the primitive streak (where gastrulation occurred), below this again is the cloacal membrane.
- Dorsally (above the notochord) lies the neural tube then ectoderm.
- Ventrally (beneath the notochord) lies the mesoderm then endoderm.
The ventral endoderm (shown yellow) has grown to line a space called the yolk sac. Folding of the embryonic disc "pinches off" part of this yolk sac forming the first primative GIT.
- The mesoderm initially undergoes segmentation to form paraxial, intermediate mesoderm and lateral plate mesoderm.
- Paraxial mesoderm segments into somites and lateral plate mesoderm divides into somatic and splanchnic mesoderm.
- The space forming between them is the coelomic cavity, that will form the 3 major body cavities (pericardial, pleural, peritoneal)
- Most of the gastrointestinal tract will eventually lie within the peritoneal cavity.
- Mesoderm and Ectoderm Cartoons
Paraxial and Lateral Plate
(Note only the righhand side is shown, lefthand side would be identical.)
(Gestational age GA 6 weeks) Carnegie stage 11
| Embryo (stage 11 ventral view)
|| Embryo (midline section)
|| Embryo (EM section) endoderm, splanchnic mesoderm, Intraembryonic coelom
|| Buccopharyngeal membrane
Stage 11 25 days, Low power ventral view of the Buccopharyngeal Membrane
Higher power ventrolateral view of the Buccopharyngeal Membrane
Close up view of the degenerating Buccopharyngeal Membrane
Stage 12 Cloacal membrane
liver contributions from endoderm and splanchnic mesoderm at the level of the transverse septum (week 4)
- Stage 11 - hepatic diverticulum development
- Stage 12 - cell differentiation, septum transversum forming liver stroma, hepatic diverticulum forming hepatic trabeculae
- Stage 13 - epithelial cord proliferation enmeshing stromal capillaries
The liver initially occupies the entire anterior body. All blood vessels enter the liver (placental, vitelline) and leave to enter the heart.
- During week 4 at the level where the stomach will form the tube begins to dilate, forming an enlarged lumen.
- The dorsal border grows more rapidly than ventral first rotation (of 90 degrees), which establishes the greater curvature of the stomach.
- A second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.
(GA 7 weeks)
- Beginning at week 5 endoderm in the GIT wall proliferates
- By week 6 totally blocking (occluding)
- over the next two weeks this tissue degenerates reforming a hollow gut tube.
- By the end of week 8 the GIT endoderm tube is a tube once more.
- The process is called recanalization (hollow, then solid, then hollow again)
- Abnormalities in this process can lead to abnormalities such as atresia, stenosis or duplications.
- Ventral mesentery lost except at level of stomach and liver.
- contributing the lesser omentum and falciform ligament.
- Dorsal mesentery forms the adult structure along the length of the tract and allows blood vessel, lymph and neural connection.
- At the level of the stomach the dorsal mesogastrium extends as a fold forming the greater omentum
- continues to grow and extend down into the peritoneal cavity and eventually lies anterior to the small intestines.
- This fold of mesentery will also fuse to form a single sheet.
- Mesoderm within the dorsal mesogastrium (week 5) form a long strip of cells adjacent to the forming stomach above the developing pancreas.
- Vascular and immune organ, no direct GIT function.
Week 8 - 10
(GA 10-12 weeks)
- neural crest migration into the wall forms enteric nervous system (peristalsis, secretion)
- midgut grows in length as a loop extending ventrally, returning as hindgut
- connected by dorsal mesentery
- rotates to form adult anatomical position (abnormalities of rotation)
- continued body growth "engulfs" the intestine by about week 11.
Normal intestinal rotation (note these are gestational age GA weeks)
Cloacal membrane (Week 4, Stage 12)
- Initially the cloaca forms a common urinary, genital, GIT space
- This is divided by formation of a septum into anterior urinary and dorsal rectal (superior Tourneux fold; lateral Rathke folds)
- hindgut - distal third transverse colon, descending and sigmoid colon, rectum.
- anal pit - distal third of anorectal canal (ectodermal)
Gastrointestinal Tract Divisions
| During the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different components of the GIT. These 3 divisions are also later defined by the vascular (artery) supply to each of theses divisions.
- Foregut - celiac artery (Adult: pharynx, esophagus, stomach, upper duodenum, respiratory tract, liver, gallbladder pancreas)
- Midgut - superior mesenteric artery (Adult: lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, half transverse colon)
- Hindgut - inferior mesenteric artery (Adult: half transverse colon, descending colon, rectum, superior part anal canal)
Gastrointestinal Tract Blood Supply
| Small Intestine length (mm)
|| Liver Growth (weight grams)
|| 1 to 124 grams (birth)
- Differentiates to form the hepatic diverticulum and hepatic primordium, generates the gall bladder then divides into right and left hepatic (liver) buds.
- Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
- Left Hepatic Bud - left lobe, quadrate, caudate (both q and c anatomically Left) caudate lobe of human liver consists of 3 anatomical parts: Spiegel's lobe, caudate process, and paracaval portion.
- Right Hepatic Bud - right lobe
- Bile duct - 3 connecting stalks (cystic duct, hepatic ducts) which fuse.
- Early liver also involved in blood formation, after the yolk sac and blood islands acting as a primary site.
- Pancreatic buds - endoderm, covered in splanchnic mesoderm
- Pancreatic bud formation – duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
- Duodenum growth/rotation – brings ventral and dorsal buds together, fusion of buds, exocrine function (postnatal function)
- Pancreatic duct – ventral bud duct and distal part of dorsal bud
- Pancreatic islets - endocrine function (week 10 onwards)
- Mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas.
- The spleen is located on the left side of the abdomen and has a role initially in blood and then immune system development.
- The spleen's haematopoietic function (blood cell formation) is lost with embryo development and lymphoid precursor cells migrate into the developing organ.
- Vascularization of the spleen arises initially by branches from the dorsal aorta.
Spleen week 8 stage 22 embryo
Enteric Nervous System
Topic covered in the neural crest lecture. Table below summarises the two major neural plexuses.
Gastrointestinal Tract Plexuses (enteric nervous system)
| Myenteric plexus
|| Submucosal plexus
| Auerbach's plexus
|| Meissner's plexus
| Leopold Auerbach (1828–1897) a German anatomist and neuropathologist.
|| Georg Meissner (1829–1905) a German anatomist and physiologist.
- first formed plexus
- lies between the outer longitudinal and inner circular smooth muscle layers of muscularis externa
- provides motor innervation to both layers
- secretomotor innervation to the mucosa
- both parasympathetic and sympathetic input
- forms 2-3 days after the myenteric plexus
- formed by cells migrating from the myenteric plexus
- innervates smooth muscle of the muscularis mucosae
- only parasympathetic fibers
| Links: enteric nervous system | intestine | neural crest | PMID 25428846
Gastrointestinal Tract Abnormalities
| USA Statistics
| USA Selected Abnormalities (CDC National estimates for 21 selected major birth defects 2004–2006)
| Birth Defects
|| Cases per Births (1 in ...)
|| Estimated Annual Number of Cases
| Spina bifida without anencephaly
| Common truncus
| Transposition of great arteries
| Tetralogy of Fallot
| Atrioventricular septal defect
| Hypoplastic left heart syndrome
| Cleft palate without cleft lip
| Cleft lip with and without cleft palate
| Esophageal atresia/tracheoesophageal fistula
| Rectal and large intestinal atresia/stenosis
| Reduction deformity, upper limbs
| Reduction deformity, lower limbs
| Diaphragmatic hernia
| Trisomy 13
| Trisomy 21 (Down syndrome)
| Trisomy 18
- Links: Human Abnormal Development | CDC Birth Defects - Data & Statistics | USA Statistics | Victoria 2004 | USA 2006 | Europe 2010
|There are several types of abnormalities that impact upon the continuity of the gastrointestinal tract lumen.
- Interuption of the lumen (esophageal atresia, duodenal atresia, extrahepatic biliary atresia, anorectal atresia)
- Narrowing of the lumen (duodenal stenosis, pyloric stenosis)
- Incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis.
- This abnormality is a very common (incidence of 1–2% in the general population) and results from improper closure and absorption of the vitelline duct during early development.
- vitelline duct (omphalomesenteric duct, yolk stalk) is a transient developmental duct that connects the yolk to the primitive GIT.
| Presents clinically in symptomatic malrotation as:
- Neonates - bilious vomiting and bloody stools.
- Newborn - bilious vomiting and failure to thrive.
- Infants - recurrent abdominal pain, intestinal obstruction, malabsorption/diarrhea, peritonitis/septic shock, solid food intolerance, common bile duct obstruction, abdominal distention, and failure to thrive.
Ladd's Bands - are a series of bands crossing the duodenum which can cause duodenal obstruction.
- Links: Intestinal Malrotation
| (intestinal aganglionosis, Hirschsprung's disease, aganglionic colon, megacolon, congenital aganglionic megacolon, congenital megacolon)
- A condition caused by the lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).
- Neural crest cells
- migrate initially into the cranial end of the GIT.
- migrate during embryonic development caudally down the GIT.
- Aganglionosis typically at the anal end of GIT.
- increased severity as it extends cranially.
| Gastroschisis (omphalocele, paraomphalocele, laparoschisis, abdominoschisis, abdominal hernia) is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera (intestines and/or organs) into the amniotic cavity.
Incidence of gastroschisis has been reported at 1.66/10,000, occuring more frequently in young mothers (less than 20 years old).
By definition, it is a body wall defect, not a gastrointestinal tract defect, which in turn impacts upon GIT development.
This indirect developmental effect (one system impacting upon another) occurs in several other systems.
- Omphalocele - appears similar to gastroschisis, herniation of the bowel, liver and other organs into the intact umbilical cord, the tissues being covered by membranes unless the latter are ruptured.
Final Thoughts- After Birth
Remember that the GIT does not function until after birth consider:
Links: Gastrointestinal Tract - Abnormalities
- ↑ Martin V & Shaw-Smith C. (2010). Review of genetic factors in intestinal malrotation. Pediatr. Surg. Int. , 26, 769-81. PMID: 20549505 DOI.
Expand the table below to see GIT related terms.
| Gastrointestinal Tract Terms
- allantois - An extraembryonic membrane, endoderm in origin extension from the early hindgut, then cloaca into the connecting stalk of placental animals, connected to the superior end of developing bladder. In reptiles and birds, acts as a reservoir for wastes and mediates gas exchange. In mammals is associated/incorporated with connecting stalk/placental cord fetal-maternal interface.
- amnion - An extra-embryonic membrane, ectoderm and extraembryonic mesoderm in origin, also forms the innermost fetal membrane, that produces amniotic fluid. This fluid-filled sac initially lies above the trilaminar embryonic disc and with embryoic disc folding this sac is drawn ventrally to enclose (cover) the entire embryo, then fetus. The presence of this membane led to the description of reptiles, bird, and mammals as amniotes.
- amniotic fluid - The fluid that fills amniotic cavity totally encloses and cushions the embryo. Amniotic fluid enters both the gastrointestinal and respiratory tract following rupture of the buccopharyngeal membrane. The late fetus swallows amniotic fluid.
- buccal - (Latin, bucca = cheek) A term used to relate to the mouth (oral cavity).
- bile salts - Liver synthesized compounds derived from cholesterol that function postnatally in the small intestine to solubilize and absorb lipids, vitamins, and proteins. These compounds act as water-soluble amphipathic detergents. liver
- buccopharyngeal membrane - (oral membrane) (Latin, bucca = cheek) A membrane which forms the external upper membrane limit (cranial end) of the early gastrointestinal tract (GIT). This membrane develops during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane lies at the floor of the ventral depression (stomodeum) where the oral cavity will open and will breakdown to form the initial "oral opening" of the gastrointestinal tract. The equivilent membrane at the lower end of the gastrointestinal tract is the cloacal membrane.
- cloacal membrane - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract.
- cholangiocytes - epithelial cells that line the intra- and extrahepatic ducts of the biliary tree. These cells modify the hepatocyte-derived bile, and are regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules. liver
- coelom - Term used to describe a space. There are extraembryonic and intraembryonic coeloms that form during vertebrate development. The single intraembryonic coelom will form the 3 major body cavities: pleural, pericardial and peritoneal.
- crypt of Lieberkühn - (intestinal gland, intestinal crypt) intestinal villi epithelia extend down into the lamina propria where they form crypts that are the source of epithelial stem cells and immune function.
- foregut - The first of the three part/division (foregut - midgut - hindgut) of the early forming gastrointestinal tract. The foregut runs from the buccopharyngeal membrane to the midgut and forms all the tract (esophagus and stomach) from the oral cavity to beneath the stomach. In addition, a ventral bifurcation of the foregut will also form the respiratory tract epithelium.
- galactosemia - Metabolic abnormality where the simple sugar galactose (half of lactose, the sugar in milk) cannot be metabolised. People with galactosemia cannot tolerate any form of milk (human or animal). Detected by the Guthrie test.
- gastrula - (Greek, gastrula = little stomach) A stage of an animal embryo in which the three germ layers (Endoderm/ Mesoderm/Ectoderm) have just formed.
- gastrulation - The process of differentiation forming a gastrula. Term means literally means "to form a gut" but is more in development, as this process converts the bilaminar embryo (epiblast/hypoblast) into the trilaminar embryo (Endoderm/ Mesoderm/Ectoderm) establishing the 3 germ layers that will form all the future tissues of the entire embryo. This process also establishes the the initial body axes. (More? Gastrulation)
- Guthrie test - (heel prick) A neonatal blood screening test developed by Dr Robert Guthrie (1916-95) for determining a range of metabolic disorders and infections in the neonate. (More? Guthrie test)
- hindgut - The last of the three part/division foregut - midgut - hindgut) of the early forming gastrointestinal tract. The hindgut forms all the tract from the distral transverse colon to the cloacal membrane and extends into the connecting stalk (placental cord) as the allantois. In addition, a ventral of the hindgut will also form the urinary tract (bladder, urethra) epithelium.
- intraembryonic coelom - The "horseshoe-shaped" space (cavity) that forms initially in the third week of development in the lateral plate mesoderm that will eventually form the 3 main body cavities: pericardial, pleural, peritoneal. The intraembryonic coelom communicates transiently with the extraembryonic coelom.
- mesothelium - The mesoderm derived epithelial covering of coelomic organs and also line their cavities.
- neuralation - The general term used to describe the early formation of the nervous system. It is often used to describe the early events of differentiation of the central ectoderm region to form the neural plate, then neural groove, then neural tube. The nervous system includes the central nervous system (brain and spinal cord) from the neural tube and the peripheral nervous system (peripheral sensory and sympathetic ganglia) from neural crest. In humans, early neuralation begins in week 3 and continues through week 4.
- neural crest - region of cells at the edge of the neural plate that migrates throughout the embryo and contributes to many different tissues. In the gastrointestinal tract it contributes mainly the enteric nervous system within the wall of the gut responsible for peristalsis and secretion.
- pharynx - uppermost end of gastrointestinal and respiratory tract, in the embryo beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches.
- recanalization - describes the process of a hollow structure becoming solid, then becoming hollow again. For example, this process occurs during GIT, auditory and renal system development.
- somitogenesis The process of segmentation of the paraxial mesoderm within the trilaminar embryo body to form pairs of somites, or balls of mesoderm. A somite is added either side of the notochord (axial mesoderm) to form a somite pair. The segmentation does not occur in the head region, and begins cranially (head end) and extends caudally (tailward) adding a somite pair at regular time intervals. The process is sequential and therefore used to stage the age of many different species embryos based upon the number visible somite pairs. In humans, the first somite pair appears at day 20 and adds caudally at 1 somite pair/4 hours (mouse 1 pair/90 min) until on average 44 pairs eventually form.
- splanchnic mesoderm - Gastrointestinal tract (endoderm) associated mesoderm formed by the separation of the lateral plate mesoderm into two separate components by a cavity, the intraembryonic coelom. Splanchnic mesoderm is the embryonic origin of the gastrointestinal tract connective tissue, smooth muscle, blood vessels and contribute to organ development (pancreas, spleen, liver). The intraembryonic coelom will form the three major body cavities including the space surrounding the gut, the peritoneal cavity. The other half of the lateral plate mesoderm (somatic mesoderm) is associated with the ectoderm of the body wall.
- stomodeum - (stomadeum, stomatodeum) A ventral surface depression on the early embryo head surrounding the buccopharyngeal membrane, which lies at the floor of this depression. This surface depression lies between the maxillary and mandibular components of the first pharyngeal arch.
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