L15 RDA Respiratory and GI development

Overview

This lecture traces the embryonic origin of the GI and respiratory systems from gastrulation and endoderm formation through gut tube formation, anteroposterior regionalisation, midgut elongation/herniation/rotation and their congenital anomalies, cloacal partitioning and its anomalies, budding and fusion of the liver, gallbladder and pancreas, and the staged prenatal development of the respiratory system. The recurring theme is that the GI and respiratory tracts are a single continuous endodermal tube that regionalises, buds and folds under reciprocal endoderm-mesoderm signalling, and that most named congenital anomalies are failures or reversals of a specific step in that folding/rotation sequence.

Origin of the gut tube from endoderm

• [Gastrulation]] occurs ~14-16 days post-fertilisation via cells involuting through the primitive streak and node:
  • Early (days 14-15): involuting cells laterally displace hypoblast cells, forming the endoderm (ventral layer).
  • Late (days 15-16): involuting cells create a new layer between ectoderm and endoderm, forming the mesoderm.
• By ~21 days the trilaminar embryo shows (outer to inner): ectoderm, lateral plate mesoderm (somatic and splanchnic components), paraxial mesoderm, intermediate mesoderm, notochord, and endoderm lining the gut. The GI and respiratory systems derive specifically from the endoderm.
• The flat endodermal sheet (~10 days) folds through intermediate stages into a tube; by ~18 days a gut tube with recognisable foregut, midgut and hindgut regions exists.
• By 18-20 days the primitive gut tube runs from the stomodeum/pharynx (anterior) through foregut, midgut and hindgut to the proctodeum (posterior), alongside the developing heart and yolk sac.
• The gut tube forms by anterior and posterior constriction of the yolk sac endoderm. Regions of the tube go on to form buds that become the lung, liver and pancreas.
• By the end of the first month, precursors to most gut structures and their derivatives already exist: stomach, lung bud, thyroid, liver, dorsal pancreas, and others.

Gut tube regionalisation

• Regionalisation occurs along the anteroposterior (A/P) axis through reciprocal interactions between endoderm and adjacent mesoderm.
• Each tissue expresses a unique combination of genes along the A/P axis; this combinatorial genetic “code” defines the region where specific structures develop (e.g. Hoxa2/3/4/5, Hoxb1, Hoxb6/8/9, Barx-1, Nkx2.5 and Hoxa/d-13, expressed at levels corresponding to the pharyngeal arches, thyroid, parathyroid, thymus, trachea, esophagus, lung buds, stomach, pylorus, duodenum, liver, pancreas, small intestine, cecum, large intestine, anal sphincter and cloaca).
• Clinical correlates:
  • Barx-1 mutations → stomach formation defects
  • Hoxd13 mutations → distal gut defects
  • Hoxa5 mutations → lung malformation

Elongation, herniation and rotation of the midgut

Timeline of gut formation:

• Regionalisation: begins early, continuous
• Elongation: lengthening of the gut tube, weeks 5-6
• Herniation: midgut extends outside the body wall, end of week 6 (~42 days)
• Rotation: end of week 7 (~50 days)
• Return and further rotation: weeks 8-10 (50-70 days)

Detail:

• Week 5: elongation occurs due to rapid growth, mainly of the midgut.
• Week 6: herniation and rotation begin.
• Herniation (~42 days): rapid midgut growth forms the primary intestinal loop, which herniates into the umbilicus and pulls the superior mesenteric artery (SMA) with it.
• Rotation part I, outside the body wall (42-70 days): the loop undergoes a 90° counterclockwise rotation, during which the small intestine moves inferiorly and to the right side while the cecum moves superiorly; the small intestine also elongates into jejunal-ileal loops.
• Rotation part II, retraction (73-77 days): the gut retracts back into the abdominal cavity while rotation continues, and the hindgut completes a 180° turn as the loop is withdrawn.
• Malrotations are incomplete or abnormal rotations of the midgut around the vitelline/superior mesenteric artery axis.

Common abnormalities of herniation and rotation:

• Nonrotation: small bowel occupies the right side of the peritoneal cavity, colon predominantly on the left.
• Reversed rotation: the normally anticlockwise rotation instead runs clockwise, so the transverse colon lies posterior to the SMA and the duodenum lies anterior.
• Subhepatic cecum: incomplete 180° rotation, leaving the cecum in a superior position.
• Congenital umbilical hernia (omphalocele): the gut returns to the abdomen but the body wall fails to cover it completely, so abdominal viscera herniate into a sac at the umbilicus.

Cloacal partitioning and its anomalies

• The cloaca is partitioned, between the end of week 5 and the end of week 7, by the urorectal septum into a ventral urogenital sinus and a dorsal rectum.
• The urorectal septum forms from two independent mesodermal folds, the Tourneux fold and the (right) Rathke fold, which converge to form the septum and the anorectal canal. After septation, the future bladder and urogenital sinus lie ventrally and the rectum lies dorsally.
• Anomalies: the primary defect is failure of the Rathke folds to form, which causes failure of the distal-most partitioning between the urogenital structures and the rectum. This produces different fistulas depending on sex:
  • Male: rectoprostatic fistula
  • Female: rectocloacal canal, or rectovaginal fistula

Formation of the liver, gallbladder and pancreas

• Endoderm-derived organs bud from the gut tube in linear order along its length:
  • Respiratory diverticulum (1 bud, ventral) → trachea and lungs
  • Hepatic diverticulum (1 bud, ventral) → liver and gallbladder
  • Dorsal and ventral pancreatic diverticula (2 buds) → pancreas
• Liver and gallbladder: the hepatic diverticulum buds from the forming midgut region of the gut tube at weeks 3-4, then branches into two divisions: the cystic division forms the cystic duct and gallbladder, and the hepatic division forms the hepatic ducts and liver.
• Pancreas: gut rotation apposes the dorsal and ventral pancreatic buds (weeks 7-8). Their ducts anastomose, the dorsal duct regresses, and the dorsal bud becomes the head, body and tail of the pancreas. The common bile duct of the liver similarly shifts position during gut rotation.
• Annular pancreas: results from abnormal ventral bud formation. The ventral pancreatic bud is bilobed and fails to rotate as a single mass; instead its two lobes wrap around the duodenum from both sides during rotation and then fuse, forming a ring of pancreatic tissue encircling the duodenum.

Development of the respiratory system

• The respiratory diverticulum forms from the anterior gut tube, just inferior to the pharynx, at weeks 3-4.
• It elongates: the superior portion becomes the trachea, while the inferior portion branches asymmetrically into lung buds and then primary bronchi.
• Further branching: secondary bronchi form at week 5, tertiary bronchi form at week 6, and branching is essentially complete by the end of week 8. By ~7-8 weeks the bronchial tree has branched into the right upper, middle and lower lobes and the left upper and lower lobes.

Airway generations correspond to named categories: generation 0 = trachea; then primary, secondary and tertiary bronchi; generations 5-12 = lower conducting airways; generations 13-15 = upper respiratory airways; generations 16-24 = alveolar ducts and alveoli.

Four phases of prenatal lung development (approximate weeks vary slightly between slides in the deck):

• Embryonic phase: weeks 4-7.
• Pseudoglandular phase: weeks 5-16/17. Higher-order bronchi form; the bronchial lumen expands by week 13; first bronchioles appear late in this phase.
• Canalicular phase: weeks 16-26. Respiratory bronchiole formation increases; differentiation of pneumocytes begins; surfactant production begins (minimal).
• Saccular phase: weeks 24/26 to birth (slides give both bounds). Alveolar ducts and alveoli differentiate; pneumocyte differentiation continues/peaks; surfactant production increases.

Preterm birth

Before 26 weeks, insufficient pulmonary surfactant is produced and the gas-exchange surfaces have not formed adequately. Surfactant production and alveolar development are not sufficient to support life outside the womb until 28 weeks. Up to 50% of infants born between 26 and 28 weeks develop respiratory distress syndrome, in which insufficient oxygen is exchanged in the lungs.

Self-test

1. Describe the fate of the cells that involute through the primitive streak during early and late gastrulation.
2. Name the germ layer that gives rise to the GI and respiratory systems, and describe its position in the trilaminar embryo.
3. Describe how the flat endoderm becomes the primitive gut tube, and name its three regions.
4. Explain the mechanism of gut tube regionalisation along the anteroposterior axis, and give one gene-mutation clinical correlate and its resulting defect.
5. List, in order with approximate timing, the five stages in the timeline of gut tube elongation, herniation and rotation.
6. Describe midgut herniation: what forms, where it herniates to, and what major vessel is carried with it.
7. Describe the two parts of midgut rotation, giving the direction and degree of rotation in each, and what happens to the small intestine and cecum.
8. Distinguish nonrotation from reversed rotation of the gut.
9. What is a subhepatic cecum, and what rotational failure produces it?
10. Describe the formation of the urorectal septum, including the two folds involved, and the two compartments it produces.
11. Explain how failure of the Rathke folds leads to different congenital fistulas in males versus females.
12. List the endoderm-derived buds of the gut tube, with the number of buds and the derivative organ(s) of each.
13. Describe how the hepatic diverticulum forms the liver and gallbladder.
14. Describe how the dorsal and ventral pancreatic buds combine to form the mature pancreas.
15. Explain the embryological mechanism that produces an annular pancreas.
16. Describe the formation of the respiratory diverticulum and its branching into the trachea, bronchi and lung lobes, with approximate weeks.
17. List the four phases of prenatal lung development with their approximate weeks and one key event of each.
18. A baby is born at 27 weeks and develops respiratory distress. Using the phase of lung development at that gestational age, explain why this occurs.

Answers

Reveal answers

1. Early (days 14-15): cells laterally displace hypoblast cells, forming the endoderm. Late (days 15-16): cells create a new layer between ectoderm and endoderm, forming the mesoderm.
2. The endoderm; it is the innermost of the three germ layers, lining the gut, deep to mesoderm (paraxial, intermediate, lateral plate) and ectoderm.
3. The flat endodermal sheet (~10 days) progressively folds through intermediate stages into a tube; by ~18 days it forms a gut tube with foregut, midgut and hindgut regions.
4. Reciprocal endoderm-mesoderm interactions produce a combinatorial gene “code” (e.g. Hox genes, Barx-1, Nkx2.5) along the A/P axis that defines where specific structures develop. Example: Barx-1 mutations cause stomach formation defects (also acceptable: Hoxd13 mutations cause distal gut defects; Hoxa5 mutations cause lung malformation).
5. Regionalisation (begins early, continuous) → Elongation (weeks 5-6) → Herniation (end of week 6, ~42 days) → Rotation (end of week 7, ~50 days) → Return and further rotation (weeks 8-10, 50-70 days).
6. Rapid growth of the midgut forms the primary intestinal loop, which herniates into the umbilicus, pulling the superior mesenteric artery with it.
7. Part I (outside the body wall): 90° counterclockwise rotation, in which the small intestine moves inferiorly and to the right side and the cecum moves superiorly (small intestine also elongates into jejunal-ileal loops). Part II (retraction): the gut retracts into the abdominal cavity while the hindgut completes a further 180° turn as it is withdrawn.
8. Nonrotation: small bowel occupies the right side of the peritoneal cavity and the colon lies predominantly on the left, with no rotation occurring. Reversed rotation: the normally anticlockwise rotation instead occurs clockwise, so the transverse colon lies posterior to the SMA and the duodenum lies anterior.
9. A subhepatic cecum results from incomplete 180° rotation, leaving the cecum in a superior position instead of its normal location.
10. The urorectal septum forms from two independent mesodermal folds, the Tourneux fold and the (right) Rathke fold, which converge; it partitions the cloaca into a ventral urogenital sinus and a dorsal rectum.
11. Failure of the Rathke folds to form causes failure of distal partitioning between urogenital structures and the rectum. In males this produces a rectoprostatic fistula; in females it produces a rectocloacal canal or a rectovaginal fistula.
12. Respiratory diverticulum (1 bud, ventral) → trachea and lungs. Hepatic diverticulum (1 bud, ventral) → liver and gallbladder. Dorsal and ventral pancreatic diverticula (2 buds) → pancreas.
13. The hepatic diverticulum buds from the forming midgut region at weeks 3-4, then branches into a cystic division (forms the cystic duct and gallbladder) and a hepatic division (forms the hepatic ducts and liver).
14. Gut rotation apposes the dorsal and ventral pancreatic buds (weeks 7-8); their ducts anastomose, the dorsal duct regresses, and the dorsal bud forms the head, body and tail of the pancreas.
15. The ventral pancreatic bud is bilobed and fails to rotate as a single mass; its two lobes instead wrap around the duodenum from both sides during rotation and fuse, forming a ring of pancreatic tissue encircling the duodenum.
16. The respiratory diverticulum forms from the anterior gut tube just inferior to the pharynx at weeks 3-4, then elongates: the superior portion becomes the trachea and the inferior portion branches asymmetrically into lung buds and primary bronchi. Secondary bronchi form at week 5, tertiary bronchi at week 6, with branching essentially complete by the end of week 8, giving the right upper/middle/lower lobes and left upper/lower lobes by ~7-8 weeks.
17. Embryonic phase (weeks 4-7): initial diverticulum/bronchial formation. Pseudoglandular phase (weeks 5-16/17): higher-order bronchi form, bronchial lumen expands (week 13), first bronchioles appear late. Canalicular phase (weeks 16-26): respiratory bronchiole formation increases, pneumocyte differentiation and minimal surfactant production begin. Saccular phase (weeks 24/26-birth): alveolar ducts/alveoli differentiate, pneumocyte differentiation peaks, surfactant production increases.
18. At 27 weeks the lungs are in the early saccular phase (just past the 26-week canalicular/saccular boundary). Sufficient pulmonary surfactant is not yet produced and the gas-exchange surfaces are not adequately formed until 28 weeks, so up to 50% of infants born between 26 and 28 weeks develop respiratory distress syndrome from insufficient oxygen exchange in the lungs.