1. The gastrointestinal tract develops from the endoderm and mesoderm germ layers. Folding of the embryo brings the endoderm inside to form the gut tube with three regions - foregut, midgut and hindgut defined by blood supply. 2. Organ buds form from the endoderm including the liver, pancreas and lungs. The mesoderm layers the gut to form the splanchnic mesoderm. 3. Patterning of the gut is regulated by Hox genes and sonic hedgehog signaling which control regional specification and formation of sphincters.

1. Gastrointestinal
System
Embryology
Larsen’s fig 14-35

2. Gastrulation:
Epiblast cells
migrate through the
primitive streak.
Definitive (embryonic)
endoderm cells displace
the hypoblast.
Mesoderm spreads
between endoderm
and ectoderm.
Langman’s fig 5.3

7. The developing endoderm (yellow) is initially open to the
yolk sac (the cardiac region is initially most anterior)…
Cranio-caudal folding at both ends of the embryo and
lateral folding at the sides of the embryo
bring the endoderm inside and form the gut tube.
Endoderm
Carlson fig 6-20

8. Folding creates the anterior and posterior intestinal portals
(foregut and hindgut, respectively)
The cardiac region is brought to the ventral side of the
developing gut tube.
cloacal membrane
Juxtaposition of ectoderm and endoderm at:
Oropharyngeal (buccopharyngeal) membrane - future mouth
Cloacal membrane - future anus
Note: there actually isn’t much mesoderm in these membranes, which is important for
their breakdown later in development to form the oral and anal orifices.
Carlson fig 6-20

9. Gut-associated organs begin to form as buds from the
endoderm: (e.g., thyroid, lung, liver, pancreas)
Midgut opening to the yolk sac progressively narrows
Carlson fig 6-20

10. By the end of the first month:
The stomach bulge is visible,
Dorsal pancreas has begun to bud
Connection of the midgut to the yolk sac is reduced to
a yolk stalk and then a very thin vitelline duct
Carlson fig 6-20

11. With lateral folding,
mesoderm is recruited to
gut wall
• Lateral folding of the embryo completes the gut tube
• Mesodermal layer of the gut tube is called splanchnic (visceral)
mesoderm - derived from lateral plate mesoderm
• Somatic mesoderm lines body cavity
Langman’s fig 6-18
Carlson fig 6-20

18. Early mesodermal patterning:
(buccopharyngeal membrane)
Specific regions of the epiblast migrate
through the streak at different levels
and assume different positions within
the embryo:
Cranial to caudal:
Notochord (n)
Paraxial mesoderm (pm)
Intermediate mesoderm (im)
*Lateral plate mesoderm (lpm)
Extraembryonic mesoderm (eem)
Langman’s fig 5-07

19. 4th week 5th week
Celiac artery supplies the foregut
Superior mesenteric artery supplies the midgut
Inferior mesenteric artery supplies the hindgut
Langman’s fig 14-14 Langman’s fig 14-4
The figure on the right also shows the mesenteries; note that the liver and stomach have
dorsal and ventral mesenteries whereas the rest of the gut has only a dorsal mesentery.

20. Foregut: pharynx thyroid
esophagus parathyroid glands
stomach tympanic cavity
proximal duodenum trachea, bronchi, lungs
liver, gallbladder
pancreas
Midgut: proximal duodenum to
right half of
transverse
colon
Hindgut: left half of urinary bladder
transverse
colon to anus
Gut tube proper Derivatives of gut tube
(These three regions are defined by their blood supply)

21. Gut = bilayered tube (endoderm surrounded by mesoderm)
Regional gut tube patterning and organogenesis require
bi-directional endoderm-mesoderm cross-talk
and inductive signals from other nearby structures
Regional patterning of the gut tube

22. Regional patterning of the gut tube - the Hox code
Hox genes are evolutionarily
conserved transcription
factors that are used in
regional patterning (flies to
mammals).
The gut has an cranial-caudal
Hox gene expression pattern
(code) similar to that seen in
neural tissue.
Some Hox genes are
expressed in mesoderm, in
overlapping patterns; some
are expressed in endoderm.
Hox gene expression
boundaries correspond to
morphologically recognizable
elements in the GI tract.
Hox gene expression is
important for formation of
major sphincters (red circles) Carlson fig 15-01

23. Hedgehog signaling is important for RADIAL
(concentric) patterning of the entire gut tube
Fetus
• High hedgehog concentration directly inhibits smooth muscle differentiation (via repression of
Smooth Muscle Activating Protein, or Smap)
• Low Hedgehog concentration is permissive of muscle differentiation in the outer wall of the gut
• High Hedgehog concentration also induces high BMP which inhibits neuron formation, thus limiting
neurogenesis initially to the outer muscular wall of the gut (later in development, SHH goes away
allowing development of the smooth muscle of the musularis mucosae and neurons of the
submucosal plexus)
Morphogen: induces different cell fates at different concentrations of signal
Adult Esophagus
Larsen’s fig 14-27
Wheater’s fig 14-5

24. Enteric Nervous System
• Collection of neurons in the GI tract.
• Controls motility, exocrine and endocrine secretion
and microcirculation.
• Regulates immune and inflammatory process.
• Functions independent of CNS.
Image from: Young. Gut 2000

25. Development of Enteric Nervous System
• Primarily derived from the vagal segment of neural crest
cells.
• Cells initially migrate to the cranial section and then
caudally
• Hindgut ganglia receive contributions of cells from the
cranial and sacral segments of the neural crest cells
• Interstitial cells of Cajal arise from the local gut
mesenchyme
Image from: http://www.landesbioscience.com/curie/chapter/2823/

26. Development of the Enteric Nervous System
• Nerve cell bodies are grouped into ganglia
• Ganglia are connected to bundles of nerves forming two plexus
• Myenteric (Auerbach’s)
• Submucosal (Meissner’s)
http://en.wikipedia.org/wiki/Enteric_nervous_system

27. Enteric Nervous System
• Myenteric plexus
• Lies between the circular and longitudinal muscles
• Regulates
• Motility
• Secretomotor function to mucosa
• Connections to
• gallbladder and pancreas
• sympathetic ganglia
• esophageal striated muscle

28. Enteric Nervous System
• Submucosal plexus
• Lies between circular muscle layer and the muscularis mucosa
• Regulates:
• Glandular secretions
• Electrolyte and water transport
• Blood flow
• Similar structure found in gallbladder, cystic duct,
common bile duct and the pancreas

29. Enteric Nervous System
• Clinical Correlations:
• Motility
• Achalasia
• Psuedo-obstruction
• Hirschsprung’s disease
• Secretions
• Cholera
• E. Coli

30. Hirschsprung’s Disease
• Congenital disorder
• 1:5000 live births
• Failure of neural crest cells to colonize the entire gut resulting in an
aganglionic zone
• Tonic constriction of aganglionic section
• Long (20%) and Short Segment (80%)
• Short segment 4:1 male:female
• Isolated anomaly in 70% of cases
• Multiple genes and modifier genes identified
• Not mendelian

31. Genetics of Hirschsprung’s Disease
• Associated genes encode members of the glial cell neurotrophic
factor family
• involved in signaling pathways
• transcription factors
• Genes identified
• GDNF
• Ret
• EDNRB
• Sox10

32. Genetics of Hirschsprung’s Disease
• Glial Cell-Derived Neurotrophic Factor (GDNF)
• Member of TGF-β superfamily
• Binds to and activates receptor tyrosine kinase (Ret)
• Defects on GDNF/Ret signaling account for
• 50% familial cases
• 30% of sporadic cases

33. Genetics of Hirschsprung’s Disease
• Endothelin 3 (Et-3) is a secreted protein expressed by gut
mesenchyme.
• Et-3 signals via Endothelin receptor B (Ednrb)
• Ednrb is expressed on migrating enteric neural crest cells
• Mutations in Et-3 and Ednrb account for 5% of cases

34. Genetics of Hirschsprung’s Disease
• Sex determining region Y – box 10 (Sox10) is a high mobility group
transcription factor.
• Expressed on migrating enteric neural crest cells
• Mutations of Sox10 account for 5% of cases

35. Genetics of Hirschsprung’s Disease
• Gene Interactions have been identified in isolated Mennonite
populations and mouse models.
• Ret and Ednrb
• Ret and Et-3
• Sox10 and Et-3/Ednrb
• Mechanisms are unknown –
• ?Downstream signaling

36. Genetics of Hirschsprung’s Disease
• Modifier Genes = Mutated gene that must be coupled with another
mutation to result in or enhance the effect.
• Neuregulin 1 (NRG1) - associates with Ret
• NRG1 signals receptors to regulate neural crest cell development. The receptor is also
associated with Sox10
• Modifiers have also been identified for Sox10 and Et-3 and Ednrb

37. Genes in Gastrointestinal Embryology
• Homeobox-containing transcription factors (Hox genes)
– play a role in gut regionalization
• Sonic Hedgehog (Shh) – transcription factor controls
endodermal-mesenchymal interactions
• Defects associated with TEF and Anorectal malformations
• Possible role in IBD and Malignancy