25) Development of the GI tract

Question 1

What is the gut?

Answer 1

• A tube from the mouth to the anus

Question 2

Why is the gut folded in a complex way?

Answer 2

• To fit 5 meters of tubing into a body which is 1 meter in length

Question 3

How are blastocysts formed?

Answer 3

• After fertilisation of gametes we have a single zygote which consists of a single cell surrounded by a protein coat (called a zona pellucida)
• The embryo undergoes a series of mitotic division which starts with 1 to form a 2-celled zygote and then a 4-celled zygote and then an 8-16-celled zygote
• This zygote is called a morula as it as a mulberry/raspberry appearance which are loosely attached.
• The embryo then undergoes compaction where the cells on the outer side will form epithelial cell tight junctions between adjacent cells.
• These tight junctions are not permeable to fluid and so can fill the central cavity of the embryo with fluid. At this point it is referred to as a blastocyst cell

Question 4

What are the different parts of a blastocyst?

Answer 4

• They consist of inner cell mass cells surrounded by a ring of cells called a trophectoderm
• The inner cell mass cells differentiate to form an epiblast layer and a hypoblast layer (primitive endoderm)

Question 5

What is the function of inner cell mass cells?

Answer 5

• They form the embryo

Question 6

What is the function of the trophectoderm?

Answer 6

• They form extra embryonic structures and so are important for implantation in the uterine wall

Question 7

What happens after implantation?

Answer 7

• Upon implantation in the uterine wall, at the start of week 3, the embryo appears as a flat disc consisting of two cells.
• The flat disc (consisting of hypoblast and epiblast) separates into two layers: the amniotic cavity (above) and the yolk sac (below)
• The flat disc is known as the germ disc or embryonic disc

Question 8

What is the direction of movement of the primitive streak?

Answer 8

• It starts near the caudal end of the embryo and will move towards the cranial end however it will only reach 3/4ths of the way through
• It can be seen under a microscope

Question 9

How is the primitive streak formed?

Answer 9

• The cells in the epiblast and hypoblast proliferate
• The cells in the epiblast condense towards the midline of the embryo and as a result become much more concentrated at the midline
• This process starts at the caudal end of the embryo
• It is these tightly packed cells that form the primitive streak
• A primitive groove forms at the midline

Question 10

What happens to the cells after forming the primitive streak?

Answer 10

• The cells at the midline undergo epithelial to mesenchymal transformation
• In this process they detach from their neighbouring cells and become mesenchymal (migratory) cells
• In doing so they fill the space between the epiblast and the hypoblast

Question 11

How do the mesenchymal cells fill in the space between the epiblast and the hypoblast?

Answer 11

• They undergo involution and ingression where they are brought in between the cell layers
• They then spread out and migrate
• While this occurs they are differentiating

Question 12

What is the function of the primitive streak?

Answer 12

• It gives rise to the germ layers

Question 13

What are the primary germ layers?

Answer 13

• Mesoderm: Forms the surrounding muscle, connective tissue and mesenteries. Formed by the primitive streak
• Endoderm (definitive endoderm): Forms the epithelium of the gut. Formed by the primitive streak
• Ectoderm: Forms the innervation of the gut and parts of our skin. They are formed by the epiblast that don’t ingress
  (We also have hypoblasts giving rise to many extra-embryonic tissue)

Question 14

What are the notochordal cells?

Answer 14

• Mesoderm cells that form a rod-like structure in the midline of the embryo
• It underlies the ectoderm and shapes the ectoderm in the midline to become neural ectoderm which gives rise to the CNS and nervous tissue in the embryo

Question 15

What is Hensen’s node?

Answer 15

• A bump at the tip of the primitive streak where the cell movements are initiated
• It has important signalling properties as it releases growth factors and other signals which shape the tissues around it

Question 16

How are tubes formed in the embryo?

Answer 16

• The gut tube is formed by the folding of sheets of cells in two directions which occur simultaneously
• The lateral edges fold in towards the midline along the cranial-caudal axis (middle axis)
• The cranial and caudal end fold inwards towards the middle of the embryo

Question 17

How does transverse folding occur?

Answer 17

• The lateral ends of the embryo fold across the cranial-caudal axis
• While this folding occurs gastrulation occurs (where the embryonic disk forms the primary germ layers
• At the end of the folding process the ends will join together and will enclose the yolk sac and allantois by pinching off the gut tube

Question 18

How is the umbilical chord formed during gut folding?

Answer 18

• The allantois and the yolk sac join together to make the umbilical cord

Question 19

What is the position of the heart during gut folding?

Answer 19

• The heart starts to form on the cranial end of the embryo

- The folding has caused the heart to move into the central (adult) position which is adjacent to the septum transversum

Question 20

What closes off the gut tube?

Answer 20

• At the cranial end it is closed by the pharyngeal membrane

- At the caudal end it is closed by the cloacal membrane

Question 21

How does the neural tube form during folding?

Answer 21

• During folding the lateral edges pinch off to form the closed neural tube which is covered by the remaining ectoderm

Question 22

What are the mesenteries formed from?

Answer 22

• Splanchnic mesoderm

Question 23

How are the mesenteries formed during folding?

Answer 23

• During lateral folding the two sides of the endoderm are brought together so that they fuse and pinch off to form an enclosed tube
• There is a mesoderm that surrounds the gut tube
• The mesoderms that connects the gut tube to the body wall is known as the mesenteries

Question 24

What are the different types of mesenteries?

Answer 24

• Dorsal mesentery: Between the dorsal (back) wall of the embryo and the gut
• Ventral mesentery: Between the ventral (front) wall of the embryo and the gut

Question 25

What is the function of the somatic mesoderm?

Answer 25

• Gives rise to somites and other body structures

Question 26

What are the different domains of the gut?

Answer 26

• Foregut: From the mouth to the caudal duodenum (top part of the small intestine) at a position called the ampulla of vater (where the common bile duct and pancreatic duct join in the duct tube)
• Midgut: Extends from the caudal part of the duodenum to about 2/3rds of the transverse colon
• Hindgut: From the last 1/3rd of the transverse colon to the anus

Question 27

What are Hox genes?

Answer 27

• Genes that confer identity in different regions of the embryo
• They are a family of transcription factors in which the proteins and their functions are highly conserved

Question 28

What is the purpose of Hox genes in the GI tract?

Answer 28

• Along the GI tract we find distinct anatomical boundaries to which we match up with gene expression domain within the embryonic phase
• Different regions of the GI tract are associated with the expression of a combination of different Hox genes
• These combinations tell the regions of the gut what structures to forms

Question 29

Where are Hox genes expressed in the GI tract?

Answer 29

• They are expressed in the mesoderm and the endoderm

Question 30

How is the gut regionalised?

Answer 30

• It is the expression of these Hox genes that start to regionalise the gut tube
• In anatomical terms the three regions of the gut are defined by their blood supply.
• All regions are supplied by the aorta
• The thoracic oesophagus is supplied by 5 arterial branches
• The foregut is supplied by the celiac artery
• The midgut is supplied by the superior mesenteric artery
• The hindgut is supplied by the inferior mesenteric artery

Question 31

How is the GI tract perfused?

Answer 31

• When the gut forms it is surrounded by a plexus (a complex network) of blood vessels which connect the vitelline vessels to the aorta
• The plexus will resolve (join together) to form the arteries that supply the GI tract from the aorta

Question 32

How is the GI tract innervated?

Answer 32

• The innervations of the GI tract follows the pattern of the blood supply
• Post-ganglionic sympathetic axons innervate the same tissues the arteries supply with blood
• The foregut is innervated by the celiac ganglion
• The midgut is innervated by the superior mesenteric ganglion
• The hindgut is innervated by the inferior mesenteric ganglion

Question 33

How does gut development take place?

Answer 33

• Regionalised development of the gut tube takes place simultaneously
• It is a dynamic process which is three-dimensional
• It is driven through growth, expansion and rotation
• Growth: Takes place at different rates in different cells of the gut. It can be outward growth (through swelling) or by lengthening of the gut tube
• Expansion: The gut can expand in different places
• Rotation: The gut can undergo complex rotations which allow it to be packed into a very tight space

Question 34

What is the difference in the terms: dorsal, ventral, anterior and posterior

Answer 34

• Dorsal and posterior mean the back surface or behind.
• Ventral and anterior means the front surface or in front
• Dorsal and ventral are used for embryos
• Posterior and anterior are used for adults

Question 35

How does the stomach develop from the embryonic stage to an adult stomach?

Answer 35

• The gut tube will start swelling asymmetrically and is more extensive towards the dorsal (back) surface of the stomach
• This causes the dorsal surface of the stomach to be convex and the ventral surface to be concave
• There are two branches of the vagal nerve (one on the left side of the stomach and the other on the right)
• Whilst swelling it also undergoes rotation in a 90 degrees clockwise direction (when looking at the stomach from the top view).
• This rotation causes the left vagal nerve to lie ventral (at the front) and the right vagal nerve to lie dorsal (back)

Question 36

What is the pylorus?

Answer 36

• A muscular sphincter at the outlet (exit) of the stomach which controls the flow of food from the stomach to the intestines

Question 37

How is the stomach present in the embryo?

Answer 37

• It is found attached to the body wall via mesenteries.
• It is attached to the dorsal section of the body wall via the dorsal mesogastrium
• It is attached to the ventral section of the body wall via the ventral mesogastrium
• The ventral mesogastrium is divided into two sections: Lesser omentum (between stomach and liver) and falciform ligament (between liver and the ventral body wall)

Question 38

How are parts of the gut fixed into place?

Answer 38

• As the stomach rotates the mesenteries are also drawn with it.
• The dorsal mesogastrium gets drawn in a 90 degrees clockwise direction
• As it continues to grow the mesogastrium encloses a space (called the omental bursa)
• The folder mesogastrium grows and fuses together to close off the omental bursa and form the greater omentum
• The greater omentum fuses with the posterior part of the body wall which fixes parts of the gut into place and makes them retroperitoneal (outside of the peritoneal space)

Question 39

What is pyloric stenosis?

Answer 39

• Obstruction of the pylorus caused by smooth muscle hypertrophy
• It is characterised by projectile vomiting after feeding
• It can be diagnosed via ultrasound and is treated by surgery or can be resolved by itself

Question 40

How does the liver bud from the foregut?

Answer 40

• Budding off of the liver from the gut is induced by signals from the heart to the ventral gut endoderm
• Hepatic diverticulum (region of gut tube that is growing out) grows into mesenchyme of septum transversum
• Chords of hepatic endoderm, bile drainage ducts, and blood vessels proliferate where they are arranged as sinusoids
• The liver then grows rapidly and exceeds the size of the septum transversum and expands into the ventral mesentery
• The falciform ligament forms between the liver and the body wall and the lesser omentum forms between the liver and stomach

Question 41

How does the pancreas bud from the foregut?

Answer 41

• The pancreas originates as two pancreatic buds. There is a dorsal bud from the duodenal endoderm (induced by notochord) and a ventral bud from the hepatic diverticulum (induced by the hepatic mesoderm)
• As the duodenum rotates, the ventral and dorsal bud meet and fuse

Question 42

How can pancreas budding go wrong?

Answer 42

• If ventral bud is bifid (bi-lobed) they can rotate inappropriately where they surround the gut tube
• This is because each lobe migrates in the opposite direction
• This forms an annular pancreas (ring shaped pancreas) which can obstruct the duodenum

Question 43

How do the intestines develop from the midgut?

Answer 43

• The intestines arise from the midgut attached throughout their length by the dorsal mesentery
• The mesentery and the gut grows at different rates (the gut tube grows quicker) along the cranial caudal axis leading to the stereotypical folding of the gut
• A ventral branch of the aorta supplies the midgut called the Superior Mesenteric Artery (SMA). With a rapid increase in length the intestines rotate around the SMA
• The growth will cause the abdomen to be too small to be accommodated in the space of the abdomen. As a result they herniate (exit from the abdominal wall) into the umbilical stalk (at 6-7 weeks)
• By week 10 the rest of the embryo catches up with growth and so the abdomen becomes large enough to accommodate the intestines allowing them to return to the body wall

Question 44

What is an umbilical hernia?

Answer 44

• When the intestines return normally but the body wall does not close over those intestines properly (rectus abdominus fails to fuse) it results in the gut being covered in skin

Question 45

What is omphalocele?

Answer 45

• Failure of intestinal loops to return into the abdomen and so the hernia is covered by the amniotic membrane
• It is commonly associated with maternal obesity, alcohol/tobacco misuse

Question 46

What is gastroschisis?

Answer 46

• Failure of the ventral body wall to fuse and so there is no covering (i.e. there is no amniotic membrane around the gut)
• Commonly associated with young maternal age, low maternal BMI and recreational drug misuse

Question 47

What is Meckel’s diverticulum?

Answer 47

• Persistence of the yolk duct (which is normally obliterated)
• It is attached to the ileum at the apex of the midgut loop
• It is usually asymptomatic
• However the diverticulum can contain gastric cells which secrete acid leading to ulceration
• It can also be connected to the umbilicus by a ligament which can lead to volvulus (where the rotation of the midgut does not proceed properly) which can obstruct the ileum

Question 48

What is Hirschsprung’s disease?

Answer 48

• A lack of parasympathetic ganglia innervation to the small intestines. This is caused by lack of neural crest cells
• These regions remain chronically/permanently constricted which leads to an enlarged colon
• This is because ganglionic innervation is responsible for inhibiting contraction of the gut and so lack of ganglia means it is constantly constricted (tonic contraction)
• It is also known as “aganglionic megacolon”.
• It primarily affects the hindgut and is characterised by the dilations of sections of the gut where there is a lack of tone and peristalsis leading to constipation

Question 49

What are neural crest cells?

Answer 49

• A transient (short lasting) population of cells in the embryo which can arise along the whole length of the embryo
• They are highly migratory and give rise to many different types of cells in the body (e.g. pigment cells, neuronal and glial cells, endocrine cells, mesenchymal cells) along with many bony structures in the head

Question 50

How are crest cells formed?

Answer 50

• They form from the neural ectoderm under the influence of the notochord
• The neural tube will roll up and the two edges of the neural tube will meet and fuse
• The cells between the neural tube and the ectoderm undergo epithelial to mesenchymal transformation
• They then migrate away from the neural tube to distant sites in the embryo

Question 51

How do crest cells migrate to and populate the gut?

Answer 51

• The vagal neural crest cells (closer to the head of the embryo) forms the vagal stream and enter through the foregut. They then migrate along the whole length of the gut
• The sacral neural crest cells (closer to the tail of the embryo) forms the sacral stream and populate the hindgut. (Defects in the sacral stream leads to Hirschsprung’s disease)

Question 52

How does the anus form?

Answer 52

• The anus develops from the cloaca.
• The cloaca is a transient structure in the embryo which represents the common end of the digestive and urogenital systems, including the base of the allantois (called urogenital sinus)
• It is covered by the cloacal membrane which covers an ectodermal depression (called the proctodeum)
• The cloacal membrane splits by the urorectal septum which gives rise to the urogenital membrane and the anal membrane
• These membrane perforate at 7-8 weeks so they can open the GI and urogenital tract

Question 53

What is an imperforate anus?

Answer 53

• When the urogenital and anal membrane do not perforate properly
• It can rise from the persistence of the anal membrane or atresia/absence of the anal canal, rectum or both