Lecture 10; Organogenesis 2 Flashcards
What are the endoderm derived organs?
Forgut
Midgut
Hindgut
What specifically does the endoderm form?
- Lining of digestive and respiratory tract
- Lining of accessory organs of the digestive
tract: liver, gall bladder and pancreas - Thyroid
What is formed by the endoderm in the forgut;
Oesophagus, stomach, upper duodenum, liver, gallbladder, pancreas
What is formed by the endoderm in the midgut;
lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, and first two-third of transverse colon
What is formed by the endoderm in the hindgut;
last third of the transverse colon, descending colon, rectum, anus
What is the function of the digestive system;
Digestion
Absorption
Excretion
What specifically happens in digestion?
Digestion
- Mechanical – breakdown of food into small pieces (mouth, stomach)
- Chemical – enzymatic digestion of food pieces into molecules (mouth, stomach, small intestine)
What specifically happens in absorption?
Absorption
Water and digested food pass into the bloodstream (small intestine – nutrients; large intestine – water, salt)
what specifically happens in excretion?
Excretion
Expulsion of undigested food (anus)
How do the germ layers contribute to the formation of the colon?
• Endoderm: Inner epithelial lining (mucosa)
• Mesoderm: Muscle, blood and lymph
vessels, connective tissue
• Ectodermal: Nerves
What are the features of the epithelium?
- Polarity: apical, basal and lateral surfaces
- Not vascularized → Nutrition via the basement membrane
- Important for secretion, absorption, protection, sensing
- Enlarged surface → microvilli (brushborder)
What are the types of epithelium?
Simple Squamous (blood vessels and alveoli) Simple Cuboidal (Kidney tubules) Simple Columnar (digestive cells)
Stratified Squamous (skin, vagina) Stratified Cuboidal (Ducts of seat glands) Stratified Columnar (mammary glands)
Where does epithelium typically form;
- Lines body surface, cavities, tubes and ducts
- High turnover of cells, highly regenerative
- Cells are tightly packed
What seals the epithelium?
- Cells are tightly bound together via the junctional complex
- Tight junctions: integral proteins of adjacent cells fuse together = impermeable
i.e cadherins, adherins, gap junctions
What is an impermeable barrier necessary?
Disruption of Barrier
• Bacterial or viral infection
• Exposure to toxins or physical insult
• Systemic diseases (e.g. IBD, leaky gut)
Describe the development of intestinal epithelium?
• Multipotent intestinal progenitor cells in the crypt give rise to all epithelial cell types.
• Zone of rapid proliferation
• Differentiation as the cells migrate up. Turnover: 3-4
days. Paneth cells migrate down, much slower turnover.
What are the cells of the intestinal epithelium?
Absorptive cells (enterocytes)
Goblet cells
Enteroendocrine cells
Paneth Cells
Formed from intestinal stem cells (proliferation in the crypts)
Differentiated cells form the villus
What is the function of enterocytes?
Enterocytes
Nutrient absorption, incl. sugar, amino- and fatty acids, ions, vitamins, water, via specific receptors and transporters located in the apical domain
What is the function of goblet cells?
Goblet cells
Mucus production Protection from HCl Lubrication
What is the function of endocrine cells?
Endocrine cells
Sensing and hormone secretion
What is the function of paneth cells?
Paneth cells
Immune defence, Secretion of anti- microbial peptides
How many types of endocrine cells are scattered through the intestinal tract?
15+ subtypes
What exactly do these endocrine cells do in in the digestive tract and sense)?
- Sensors for composition of luminal content and regulate the secretion of hormones accordingly
- Receptors on the apical side, respond to fatty acids, amino acids, sugars, bile, calcium
What do endocrine cells of the digestive tract release?
• Upon stimulation, hormones are secreted from the basal membrane
- Systematic distribution via bloodstream - Direct activation of nerves
- Paracrine signalling
Whats an example of an digestive tract hormone?
Cholecystokinin (CCK)
Where is Cholecystokinin (CCK) released from?
Stomach
What causes the production of Cholecystokinin (CCK) and whats its function?
- Produced in response to fat and protein
- Inhibits the stomach from emptying
- Stimulates secretion of bile and pancreatic
enzymes to facilitate fat and protein digestion
→ modulates appetite
What does exogenous CCK do?
Exogenous administration of CCK decreases meal size. But: effect is short-lived, as CCK degrades rapidly.
What mediates patterning in embryonic development?
• Mediated by morphogens = secreted growth factors or chemicals that diffuse from a source and form a gradient
What does the gradient of morphogens do?
- Gradients of morphogens induce - Cascades of transcription factors regulate - Positional patterning of organs
What is regionalisation;
Crosstalk between endo- and mesoderm
Mesoderm secretes morphogens, incl. FGF, BMP, Wnt
A-P patterning of the primitive gut tube, into broad domains
(foregut,midgut,hindgut)
How are patterns translated into organs?
Transcription factors are induced along morphogen gradients
→ Broad domains are progressively refined into smaller domains where organs will form
What are some examples of growth factors?
FGF2
RA
Wnt, FGF4, BMP
Describe FGF2 expression;
FGF2
- High: lung and thyroid
- Low: liver, pancreas and small intestine
Describe RA expression
Retinoic acid (RA) - High: lung, stomach, pancreas, liver - Defines midgut – hindgut boundary - Low: small and large intestine
Describe Wnt, FGF4, BMP signalling
Wnt, FGF4, BMP
- Induce mid- and hindgut-derived organs
What is a good animal model for embryonic development?
Zebrafish
How related is the zebrafish to humans?
- 70% of protein-coding human genes are related to genes found in zebrafish
- 84% of genes known to be associated with human disease have a zebrafish counterpart
What happens when zebra fish embryos were soaked in RA inhibitor?
Lower concentration of RA has shifted the small intestine segment further anterior
Describe the formation of the intestinal epithelium;
• Antagonizing Wnt (proliferative compartment) and BMP (differentiated compartment) gradients establish the crypt – villus axis
- Cell migration through zone of proliferation into differentiation
- Crypts become the niche for stem cell maintenance
Wnt = development
BMP=maintainence
Describe the differentiation of stem cells into enterendocrine cells;
Intestinal stem cell (multilineage potential)
MATH 1 (Secretory progenitor) (tri-lineage potential)
Ngn3 (early endocrine progenitor) (unilineage potential)
NeuroD (committed endocrine precursor)
Enteroendocrine cells
What other cells can be formed instead in the endocrine fate lineage?
Notch signalling (acts between two fates) can cause these stem cells to form Enterocytes instead
Also MATH1 can form paneth / goblet cells instead of Ngn3
Describe the signals that play a role in the stepwise endocrine fate of intestinal stem cells;
→ Transcription factors act sequentially to specify fates
→ Notch acts as a switch between two fates
Describe the signals that play a role in the stepwise endocrine fate of intestinal stem cells;
→ Transcription factors act sequentially to specify fates
→ Notch acts as a switch between two fates
(fate restriction is that action of signals and transcription events reducing the potential of cells)
How is the homeostasis of epithelium maintained?
- Maintenance of a tissue during adult life
- Epithelia – high turnover and regeneration → proliferation needs tight control
=signals!
What are some examples of signals that maintain epithelium homeostasis?
Wnt: key factor for maintenance of the crypt / stem cells
Loss of Wnt → no crypts, small villi, all enterocytes
Gain of Wnt → ???
What does hyperactive wnt sinalling lead to?
Mutation of APC gene, leads to over activation of Wnt→ uncontrolled proliferation at the expense of differentiation
What is the most frequent cause of colorectal carcinoma?
Loss of APC
