Embryology
Specialization of the Different Domains of the Primitive Gut Tube is Initiated by Organ-Specific Transcription Factors Expressed in Different Regions
Table 1: Genes Involved in Early Liver, Bile Duct, and Pancreas Development
| Gene | Derivation | Possible Function | Chromosome |
|---|---|---|---|
| BMP | Bone morphogenic protein | Growth factor family; multifunctional role | Ch6 |
| FGF | Fibroblast growth factor | Growth factor family; multifunctional role | Ch10 (depends on member) |
| VEGF | Vascular endothelial growth factor | Acts on endothelial cells, increasing permeability and inducing angiogenesis | Ch6 |
| PDX1 | Pancreas/duodenum homeobox protein 1 | Transcription factor; pancreas development | Ch13 |
| HES-1 | Hairy and enhancer of split 1 (Drosophila) | Transcription factor family; target of Notch signaling | Ch3 |
| PROX-1 | Prospero homeobox 1 | Homeobox transcription factor; needed for hepatocyte formation | Ch1 |
| HNF-6 | Hepatocyte nuclear factor 6 (ONECUT-1) | Transcription factor; needed for cholangiocyte formation | Ch15 |
| NOTCH1-4 | Mutation produced irregular ("notches") in wing tips of Drosophila | Receptors for signaling network, regulates interactions between physically adjacent cells | Ch9 |
| NEUROG3 | Neurogenin 3 | Basic Helix-loop-helix transcription factor; essential for endocrine lineage | Ch10 |
| SOX-9 | SRY (sex determining region Y)-box 9 | Forms DNA-binding proteins; needed for cholangiocyte differentiation | Ch17 |
| WNT | Wg & Int standing for wingless-related integration (Drosophila) | Growth factor family; multifunctional roles | Ch10 (depends on member) |
| SHH | Sonic hedgehog | Early embryonic patterning, cell proliferation, and survival | Ch7 |
| LGR-4 | Leucine-rich repeat containing G protein-coupled receptor | Gallbladder maturation | Ch11 |
| PAX-6 | Paired box - 6 | Transcription factor; for endocrine cell lineage | Ch11 |
| C/EBPβ | CCAAT/enhancer binding protein | Transcription factor; needed for hepatocyte formation | N/A |
| PTF1A | Pancreas-specific transcription factor 1A | Transcription factor; pancreas development | Ch10 |
Table 2: Specialization of the Different Domains of the Primitive Gut Tube
| Transcription Factor | Organ |
|---|---|
| SOX 2 | Esophagus and stomach |
| NKX2.1 | Lungs |
| PDX1 and PTF1A | Pancreas |
| HHEX | Liver |
| CDXC | Small bowel |
| CDXA | Large bowel and rectum |
The definitive endoderm is formed at the ventral side of the vertebrate embryo during gastrulation. Evagination of the endoderm at the anterior end of the embryo generates the ventral foregut, which will eventually give rise to the liver, lung, thyroid, and the ventral pancreas. The dorsal region of the definitive endoderm develops into the intestines and the dorsal pancreas
- CK -19 is a marker for bile duct cells = used for Cholangiocarcinoma
Embryology and Development of the Liver, Biliary Tree, and Pancreas (sabiston)
Normal Development and Embryology
- Common Progenitor
- The liver shares a common progenitor with the biliary tree and pancreas.
- Signaling Molecules
- Signals from the cardiac mesenchyme and septum transversum regulate development.
- Key molecules involved include:
- Fibroblast Growth Factor (FGF)
- Bone Morphogenetic Protein (BMP)
- Wnt
- Tissue Growth Factor Beta (TGF-ß)
- Formation of the Liver Primordium
- Begins in the third week of development.
- Arises as an outgrowth of endodermal epithelium, known as the hepatic diverticulum or liver bud.
- Development of the Bile Duct
- The connection between the hepatic diverticulum and the future duodenum narrows to form the bile duct.
- An outpouching of the bile duct forms the gallbladder and cystic duct.
- Hepatic Sinusoids Formation
- Hepatic cells develop cords and intermingle with the vitelline and umbilical veins to form hepatic sinusoids.
- Formation of Other Liver Structures
- Hematopoietic cells, Kupffer cells, and connective tissue form from the mesoderm of the septum transversum.
- As the liver protrudes into the abdominal cavity, these structures are stretched into thin membranes, forming:
- Falciform ligament = derived from septum transversum (MCQ)
- Lesser omentum
- Visceral Peritoneum and Bare Area
- The mesoderm on the surface of the developing liver differentiates into visceral peritoneum.
- Superiorly, contact between the liver and mesoderm (future diaphragm) is maintained, forming a bare area devoid of visceral peritoneum.
Multiple Choice Question (MCQ)
Answer: c. Third week of development
Explanation:
- The liver primordium, or liver bud, begins to form in the third week of development as an outgrowth of endodermal epithelium.
Figure Reference
Figure 54.2: Depicts the liver's development, including the hepatic diverticulum, bile duct formation, hepatic sinusoids, and associated mesoderm structures forming the falciform ligament and lesser omentum. The bare area of the liver, where it contacts the diaphragm, is also shown.
This information provides a detailed overview of the embryological development of the liver, biliary tree, and pancreas, highlighting key stages, signaling molecules, and structural formations.
Fetal Circulation and the Role of the Primitive Liver
Primitive Liver and Fetal Circulation
- Vitelline Veins
- Carry blood from the yolk sac to the sinus venosus.
- Form a network around the foregut (future duodenum) that drains into hepatic sinusoids.
- Eventually fuse to form the portal, superior mesenteric, and splenic veins.
- Sinus Venosus
- Empties into the fetal heart.
- Becomes the hepatocardiac channel (MCQ) , then the hepatic veins and retrohepatic inferior vena cava (IVC).
- Umbilical Veins
- Paired early in development.
- Carry oxygenated blood to the fetus.
- Initially drain into the sinus venosus.
- At week 5, begin to drain into hepatic sinusoids.
- Right umbilical vein disappears.
- Left umbilical vein drains directly into the hepatocardiac channel via the ductus venosus, bypassing hepatic sinusoids.
- Remnants in the Adult Liver
- Left Umbilical Vein: Becomes the ligamentum teres (MCQ) , running in the falciform ligament into the umbilical fissure.
- Ductus Venosus: Becomes the ligamentum venosum (MCQ) , terminating under the left liver at the termination of the lesser omentum.
Figure Reference
Figure 54.3:
- A: Shows the umbilical and vitelline vein development of a 5-week-old embryo, illustrating the hepatic sinusoids and their drainage pathways.
- B: Depicts the vitelline veins' direct drainage into hepatic sinusoids in the second month, the formation of the ductus venosus, and the oxygenated blood bypassing the hepatic sinusoids.
- C: Illustrates the developed portal system (portal, superior mesenteric, and splenic veins), the disappearance of the right umbilical vein, and the left umbilical vein bypassing hepatic sinusoids via the ductus venosus.
Multiple Choice Question (MCQ)
Which vein disappears during development, leading to the left umbilical vein draining directly into the hepatocardiac channel?
a. Left vitelline vein
b. Right umbilical vein
c. Left umbilical vein
d. Right vitelline vein
Answer: b. Right umbilical vein
Explanation:
- The right umbilical vein ultimately disappears during development, allowing the left umbilical vein to drain directly into the hepatocardiac channel via the ductus venosus, bypassing the hepatic sinusoids.
Pancreas
Molecular Factors and Pathways in Pancreatic Organogenesis
- Key Genes and Their Roles
- PDX1
- Critical role in exocrine differentiation.
- Knockout mice develop primitive pancreatic buds but not the organ.
- PTF1
- Coexpression with PDX1 determines progenitor cell fate.
- Notch Signaling Pathway
- Suppresses endocrine differentiation.
- Promotes exocrine development via induction of Hes1 transcription factor.
- Prolonged Notch expression prevents acinar formation.
- Hedgehog Pathway
- Inhibition in PDX1-positive cells leads to endoderm differentiation into pancreas.
- Wnt Pathway
- Crucial in all aspects of pancreatic development.
- Lack of Wnt signaling results in varying levels of pancreatic agenesis.
- Neurogenin 3
- Drives endocrine lineage differentiation.
- Arx and Pax-4
- Arx: Promotes α/PP cell differentiation.
- Pax-4: Promotes β & δ cell differentiation.
- PDX1
Embryologic Development of the Pancreas
- Timeline and Process
- Fourth Week of Gestation
- Development of the exocrine pancreas begins.
- Pluripotent pancreatic epithelial stem cells give rise to exocrine, endocrine cells, and ductal network.
- Dorsal and Ventral Bud Formation
- Dorsal bud appears first, developing into the superior head, neck, body, and tail.
- Ventral bud develops as part of the hepatic diverticulum, forming the inferior head and uncinate process.
- Fusion of Buds
- Between the fourth and eighth weeks, the ventral bud rotates posteriorly and fuses with the dorsal bud.
- By the eighth week, the dorsal and ventral buds are fused.
- Fourth Week of Gestation
Figure References
- Figure 56.1
- Depicts the molecular factors and pathways associated with pancreatic organogenesis.
- Figure 56.3
- A: Shows the initial appearance of dorsal and ventral pancreatic buds from the primitive duodenal endoderm.
- B: Illustrates the rotation of the ventral bud to fuse with the dorsal bud.
- C: Demonstrates the fused dorsal and ventral buds forming the mature pancreatic ducts (main and accessory pancreatic ducts).
Multiple Choice Question (MCQ)
Answer: b. PDX1
Explanation:
- PDX1 is essential for exocrine differentiation. Knockout mice develop primitive pancreatic buds but fail to form the complete organ.
Spectrum of Pancreas Divisum
- Normal Pancreatic Duct Anatomy
- A: Normal duct with the duct of Santorini
- The normal configuration where both the main pancreatic duct (duct of Wirsung) and the accessory duct (duct of Santorini) are present.
- B: Normal duct without the duct of Santorini
- The normal configuration where only the main pancreatic duct (duct of Wirsung) is present, and the accessory duct is absent.
- A: Normal duct with the duct of Santorini
- Pancreas Divisum Variants
- C: Pancreas divisum
- The dorsal and ventral ducts remain separate.
- The duct of Wirsung drains the uncinate process and head of the pancreas into the major papilla.
- The duct of Santorini drains the majority of the head of the pancreas.
- D: Dorsal duct only
- The dorsal duct is the only functional duct.
- The duct of Wirsung is absent.
- E: Functional pancreas divisum
- There is a filamentous communication between the ducts, allowing some degree of drainage from both ducts.
- C: Pancreas divisum
Figure Reference
Figure 103.6:
- Illustrates the spectrum of pancreas divisum, including the normal duct anatomy and various configurations of pancreas divisum.
- A: Normal duct with duct of Santorini
- B: Normal duct without duct of Santorini
- C: Pancreas divisum with separate dorsal and ventral ducts
- D: Dorsal duct only, with the duct of Wirsung absent
- E: Functional pancreas divisum with filamentous communication between ducts
Multiple Choice Question (MCQ)
Answer: c. Pancreas divisum with separate dorsal and ventral ducts
Explanation:
- The most common variant of pancreas divisum involves the dorsal and ventral ducts remaining separate. In this configuration, the duct of Wirsung drains the uncinate process and head of the pancreas into the major papilla, while the duct of Santorini drains the majority of the head of the pancreas.