Embryology Flashcards
What are the prerequisites for development ie to increase in size and complexity
Capacity to increase cell number
Capacity for differentiation
Capacity to organise in long range structures
What is menstrual age
From the first day of last menstrual period
What is conceptual/ fertilisation age (used most in lectures l)
Timing from first day of fertilisation
When are the foetal and embryonic stages?
Embryonic: first 2 months
Foetal: last 7 months
What are the Carnegie stages
A standardised system of 23 stages of development based upon anatomical features in the embryonic phase
What happens on day 0
Fertilisation
When is implantation
Day 7
When does gastrulation occur
Day 14
When is the beginning of neurogenesis
Day 16
When is the first functioning organ formed
Day 22 when the heart begins to beat
When does neural tube close occur
Day 27
When is quickening? What does this mean?
Day 112/ Week 16
Mother begins to feel movements of the foetus
When does the foetus become viable
Day 161/ week 23
Over which weeks does gastrulation and neurogenesis occur
3-8
Where does fertilisation occur and what does it result in
In the Fallopian tube forming a zygote
What happens day 3 (how many cells)
8 cell stage: embryo activates the genome (embryonic genome activation (EGA))
On day 4 compaction occurs and intercellular signalling begins
What does the first lineage decision establish
The trophoblast and inner cell mass
What does the second lineage decision make
Pluripotent epiblast and extraembryonic hypoblast
What does the hypoblast give rise to
The yolk sac
What happens days 6-7
Embryo hatches from zona pellucida and is now ready for implantation
Give the 3 populations in the late blastocyst
Epiblast
Hypoblast
Trophoblast
What is implantation
What kind of implantation do humans undergo
Attachment of late blastocyst to the uterus
Interstitial implantation with the blastocyst penetrating the endometrial lining
What does the epiblast specify and form
Amnion, forming the amniotic cavity and gives rise to the embryonic disc
What happens to hypoblasts
Expand and form the primary and secondary yolk sac
What does trophoblast diversify into
Cytotrophoblast and syncytiotrophoblast
What are lacunae
Cavities in the syncytiotrophoblast, which play an important role in embryo nutrition prior to development of the placenta
3 germ layers?
Ectoderm - outermost layer
Mesoderm- middle layer
Endoderm- innermost layer
What is induction
One cell type (the inducer) induces the fate of another cell type (responder)
What coordinates gastrulation
Hypoblast
What does the ectoderm form
Skin and nervous system
What does the mesoderm form
Muscles, connective tissue, bones and circulatory system
What does the endoderm form
Digestive and respiratory system + other internal organs
What is the gut formed from
The inner of the 3 concentric tubes generated when the 3D embryo is formed (ie the endoderm)
What does the gut tube initially consist of
Blind ending tubes at the cranial and caudal ends and a central portion, the midgut that still connects to the yolk sac
Where does the foregut terminate
The buccopharyngeal membrane (which goes on to form the mouth and nose)
Where does the hind gut end
The cloacal membrane
What does the cloacal membrane go on to form
urogential and rectum
What forms the thoracic part of the foregut
The stomach
Which side of the stomach grows faster
The dorsal wall grows faster than the ventral wall resulting in the ventral lesser curvature and dorsal greater curvature
What happens after the curvature of the stomach is formed
It undergoes a 90 degree rotation about the cranio-caudal axis so that the greater curvature lies on the left and the two branches of the vagus nerve that were left and right now lie anterior and posterior respectively
There is an additional tilting caudally which orientates the great curve so that is inferior
What is formed as a result of stomach rotation
The lesser sac
Discuss pyloric stenosis
3/1000 affected
Male babies 2-8 weeks most at risk
Symptoms: forced projectile vomiting leading to severe dehydration
Requires surgery
Where does the hepatic diverticulum sprout from
What happens next
The duodenum into the ventral mesentery
Interacts with the surrounding septum transversum mesenchyme
What does the liver bud require
An indicative signal from the heart mesoderm
How do we know that heart mesoderm is essential for inducing liver development
If early pre liver endoderm is explanted with Pre liver mesoderm alone, no liver differentiates but with both pre-heart and - liver mesoderm, well formed hepatic cords develop
What are the signals from the heart mesoderm to the developing liver
Growth factors eg FGF1 and FGF2
Also promote liver specific gene transcription by blocking inhibitory factors present in the endoderm
What happens after hepatic specification
Endothelial cells intercede between hepatic endoderm cells and the septum transversum mesenchyme. They promote the morphogenesis phase of organogenesis
What happens in the morphogenesis phase of hepatic development
Hepatogenic cells multiply and migrate into the septum transversum mesenchyme to develop the liver bud and ducts
What happens to the lateral plate mesoderm surrounding the newly formed liver bud
Becomes the supporting stroma
What is the cystic diverticulum
It sprouts from the base of the hepatic bud and forms the gall bladder and cystic duct
Give an overview of the development of the pancreas
Forms from 2 buds: dorsal (forms first) and ventral (grows more slowly)
Buds are induced by endoderm, adjacent mesoderm and ectoderm (eg notochord) allowing them to emerge and develop
Then first pancreatic-specific genes (eg Pdx1) are expressed
Exocrine and endocrine tissue is formed
2 buds eventually fuse when the smaller ventral bud migrates round and meets the dorsal bud
What does exocrine pancreatic tissue produce
Amylase and α- fetoprotein
What does endocrine pancreatic tissue produce
Insulin
Glucagon
Somatostatin
What regulates the ratio of exo to endocrine cells
Follistatin which is secrete by the pancreatic mesenchyme
What forms the uncinate process
The pancreatic ventral bud
What is an annular pancreas
Give a complication and it’s incidence
If the ventral bud is duplicated migrating lobes can encircle the duodenum
Affects 1/7000 people
May result in narrowing or constriction of duodenum
Why does herniation occur in gut development
The extensive growth of the midgut, especially the ileum, leads to it growing faster than the abdomen and the primary intestinal loop formed is forced out into the umbilical cord, carrying with it the superior mesenteric artery
What happens to the developing herniated loop
Rotates 90 degrees anti-clockwise (programmed by left right organisation)
The continued lengthening of the duodenum and the jejunum gives rise to a series of folds and the midgut is retracted, rotating a further 90
Finally the caecum moves inferiorly, completing the 270 degree rotation
What is omphalocele
When the umbilical ring doesn’t close and the loop of midgut remains outside the abdominal wall in a peritoneal sac
What is Mickel’s Diverticulum
Finger like pouch on antemesenteric border of ileum
It is a failure of the Vitelline duct to regress completely
It may rotate and obstruct
What can abnormal gut rotation lead to
What is needed to diagnose
Freely suspended coils of intestine prone to torsion or volvulus
Barium meal/ enema
Where does the kidney develop from
What are its 3 phases of development
The intermediate mesoderm
Pronephros -> mesonephros -> metanephros
When does the urogential ridge begin to form and in what direction
In week 4 in a rostral caudal direction
Discuss pronephros development
Begins to develop at day 24 between somites 3-5 with the duct forming between somites 5-7
It is a rudimentary structure in higher vertebrates but is essential for embryonic survival of fish and amphibians
It degenerates v rapidly and is never functional in humans
Discuss the development of the mesonephros
Differentiates from ~28 days and begins to regress at the cranial end at 5 weeks
Never has more than 30 nephrotomes
It produces dilute urine
Briefly describe metanephros development
Ureteric bud grows out of the mesonephric duct at ~5 weeks and induces formation of the metanephric kidney
How do the tubules in the mesonephros form
In cranio-caudal succession
Earlier tubules degenerate as later ones form so usually ~30 tubules at any time
Is the mesonephros functional
Yes it is functional in the embryo, producing a dilute urine important in maintaining the composition of amniotic fluid
How can you show experimentally what induces Kidney development
By artificially placing a barrier between the ureteric bud and surrounding cells to stop movement of secreted proteins stops kidney development
Define induction
Alteration of the fate of a cell or tissue by interaction with a second
What are the phases of initiation
Give a description of each in the context of kidney development
Initiation: signals from metanephrogenic mesenchyme induce growth of ureteric bud
Commitment to development: response to inducing signals - proliferation and differentiation of bud and mesenchyme
Morphogenesis: in response to signals from mesenchyme bud commences branching morphogenesis, mesenchyme responds by becoming epithelial in nature and forming nephrons
Give the 2 key consequences of induction in kidney development
Ureteric branching morphogenesis
Epithelial morphogenesis
Describe the epithelial morphogenesis in kidney development
The mesenchyme to epithelial transition occurs in response to Wnt expression
Formation of S shaped bodies
Thins on one side to form glomerulus
Fuses with UB tip
Extends to form proximal and distal tubules
What causes outgrowth of ureteric bud towards metanephrogenic mesenchyme
Production of glial derived neurotrophic factor (GDNF) by MM which binds to the Ret receptor expressed on ureteric buds
What does the ureteric bud induce the mesenchyme to do
Condense around the tips of the branching ureteric epithelium and time undergo MET to form renal vesicles
What is MET
Mesenchyme to epithelial transition
What triggers MET
What does this do
Wnt signalling via secretion of Wnt9b from the ureteric tip
Upregulates (Fgf8) and Wnt4 production by the MM
What does Fgf4 do
Stimulates proliferation of mesenchyme
What does Wnt4 do
Regulates formation and differentiation of the comma and S shaped bodies to form renal vesicles
What follows induction at the ampulla in kidney development
The bud branches and a nephron forms
What is dichotomous branching
What does it give rise to from the ureteric bud
Branching that results in the regular form of the kidney
It gives rise to the collecting ducts while the surrounding cells wil form the nephron and convoluted tubules
When does the mean glomerular number level off
Is this the end of kidney development
36 weeks
No, nephrogenesis and functional maturation continues after birth
What is the differential lineage if nephron cells
There are different lineages;
Collecting duct is from the ureteric bud
Convoluted tubules and glomerulus from the metanephric blastema
Where do renal blood vessels come from
Smaller vessels are derived by vasculogenesis within the kidney
Larger vessels were developed by angiogenesis and invaded the kidney from the renal arteries
How common is developmental abnormality in the urinary tract
Do all cause clinical problems
10% of all new norms
No but if the ureteric bud does not reach/ signal properly to mesoderm the kidneys don’t form (agenesis)
What are polycystic / dysplastic kidneys
Kidneys whose tubules failed to form correctly and may continue to proliferate
Bifurcated ureters may also occur due to defects in induction
What is the mean globular number at 15 and 40 weeks and then in the adult
How does this relate to disease
15:15000
40: 740000
Adult: 617000 (declines with age)
Related to risk of hypertension
Genetically induced reduction in nephron number in mice is associated with high blood pressure
Number of nephrons is strongly related to birth weight
How are nephron number and birth weight related
Babies with birthweight below 10th percentile have 30% fewer nephrons
This is the developmental programming hypothesis
What happens after the mesonephric duct and ureteric bud enter the urogential sinus
In the Male the mesonephric duct migrates inferiorly to enter urethra Asia has deferens But regresses in females
Ureteric bud grows and elongates to become ureter and the portion closest to the urogential sinus splays out to generate posterior bladder wall
What is the trigone
The posterior wall of the bladder
Discuss the urachus in the foetus
It constitutes the connection between the developing bladder and the allantois, so runs from the bladder to the umbilicus and umbilical cord
What happens to the urachus
Normally fibroses after delivery forming the median vesical ligament
If this fails a urachal fistula May develop, resulting in urine leaking from the umbilicus
Where do the gonads develop
On the medial side of the mesonephric ridge (the urogential ridge)
When does te genital ridge firm
When do gonads differentiate
5-6 weeks
On medial side of mesonephros
After 7-8 weeks of gestation
Associated with dual ductal system
Why is urogential development associated with a dual Ductal system
Wolffian (mesonephric) ducts firm first Then Mullerian (paramesonephric) ducts Form laterally
Ducts form by invagination of the coelomic epithelium
Do primordial germ cells begin at genital ridges
No they migrate by amoeboid movement from the hindgut along the dorsal mesentery around weeks 4-6
They are guided by chemitaxis
What does sex determination depend upon
Presence or absence of Y chromosome
What allows Y and X to pair at meiosis
Y retains homology with X at telomeres as they arose from a common ancestor
What are the gonadal and somatic sex structures in males
Gonadal: testis
Somatic: penis, scrotum, prostate, vasa
What are the gonadal and somatic sex structures in females
Gonad: ovary
Somatic: clitoris, vagina, uterus, oviducts
Where is SRY located
What does this position allow
Near the end of the short arm of Y
Allows SRY to be exchanged in crossover events between X-Y or completely lost
Exchange can lead to sex reversal
What are the 3 phases of limb development
Limb bud outgrowth and patterning
Morphogenesis
Growth
What do limb buds consist of
A core of loose Mesenchyme and and an ectodermal layer
What is the AER
The apical ectodermal ridge
A thickening of ectoderm the tip of the developing limb
Plays a critical role in outgrowth
What does removal of the AER do
Leads to a truncated limb
The earlier the AER is removed the less developed the limb is
This suggests AER produces a signal promoting proximal distal development of the limb
What happens if a chick’s AER is grafted onto the lower limb bud in place of leg AER
Give another example to prove the same effect
Bud will still produce a leg
Mouse AER can substitute for chick AER
Which is the important protein secreted by the AER
How do we know this
FGF8
If AER is replaced by bead of FGF8 an almost normal limb still develops
What is FGF4
Works similarly to FGF8 and is expressed in posterior AER
Why does older mesenchyme give more distal structures?
The structures formed depend on the length of time exposed to FGF
Cells close to the FGF source remain undifferentiated and don’t differentiate until out of reach of FGF
Cells exiting first form proximal structures, cells exposed for longest form distal structures
What is SHFM
Split Hand Foot Malformation
Rare limb condition linked to AER failure
Discuss thalidomide’s effect on development
Prevents proliferation of cells in progress zone so cells are exposed to FGF for longer and develop as more distal structures (phocomelia - a loss of proximal limb structures)
Where is the AER located
Boundary between dorsal and palmar on limb bud
How is dorsal palmar patterning coordinated
Ectoderm produces signals to confer dorsal/ palmar information
Wnt7a is produced by dorsal part only. This diffuses into the mesoderm where it induces expression of genes that coordinate dorsal fates
Describe 2 experiments showing the importance of Wnt7a and the ectoderm in dorsal palmar development
If ectoderm is removed and replaced back to front, hand develops back to front
If Wnt7a is removed in mouse embryos, double ventral limbs develop
What happens if you graft the posterior zone of one limb into the anterior of another limb
It leads to a limb with mirror image duplication of digits
This is affected by position of graft, which suggests the cells produce a diffusible signal and the type of digit formed depends on the concentration of signal that the cell is exposed to
What is the morphogen concept
the cells produce a diffusible signal and the type of digit formed depends on the concentration of signal that the cell is exposed to
Which signal is important in digit formation and patterning (ZPA)
Prove it
Sonic Hedgehog
SHH transplantation shows that number and identity of digits formed depends on concentration of SHH
What causes polydactyly
Mutated SHH
What regulates Hox genes
SHH regulates their expression
Discuss Hox genes
Which are important for limb development
Found in 4 clusters in mammals (a-d)
Hox d
What results in syndactyly
What is it and how is it treated
Mutated Hox d13
Results in fusion of digits
Zig zag incisions to give skin flaps to cover cut region
What do the initial phases of skeletogenesis involve in the limbs
Formation of cartilage condensations regulated by GDF5
Bone Initiates in the mesenchyme, GDF5 increases condensation
What happens if you abnormally increase GDF5
Abnormal bone growth / thickening
What is CGT and CHTT
Chondrodysplasias Grebe type
And Hunter Thompson type
Caused by mutations in GDF5
Pronounced shortening of skeletal elements
How is cartilage converted to bone
Ossification
Growth hormone, thyroid hormones and IGF1 all influence bone growth by acting on germinal zone stem cells
FGF3 inhibits growth and promotes differentiation
Where is the FGF3 receptor present
Chondrocytes
What causes dwarfism
Achondroplasia is associated with an activating mutation in FGF3R
What happens if FGF is exposed to the flank
A new limb grows with AER and ZPA
What ensures limbs grow in the right place
Tbx5 expression
Defects in Tbx5 are associated with Holt Oran syndrome
Which limbs position upper and lower limbs
Tbx5 = upper Tbx4 = lower
When does the zygote undergo cleavage
What is this
Days 1-5
Cell division in the absence of cellular growth. There is no increase in total cell mass
Which part of the fertilised egg is cleavage dependent on
The large cytosolic compartment
What happens at day 3
This is the 8 cell stage
Here the human embryo activates the genome
What is EGA
Embryonic genome activity
When does compaction occur
How many cells are there here
Day 4
8
When does cavitation occur
What also happens here
Day 4-5
The morula becomes the early blastocyst
The first lineage decision occurs here
What does the first lineage decision establish
Trophoblast and Inner Cell Mass (ICM)
What is the trophoblast and what does it give rise to
What does the ICM form
An extra embryonic lineage
Gives rise to the placenta
ICM forms the embryo
What happens days 6-7
ICM undergoes 2nd lineage decision
The embryo hatched from the zona pellucida
at the second lineage decision, what does the ICM differentiate into
The pluripotent epiblast and the extraembryonic hypoblast
What does the hypoblast give rise to
What about the epiblast
The yolk sac
The epiblast is the founding population of the entire foetus
When is the embryo ready for implantation
Days 6-7 when the embryo hatched from the zona pellucida
The human late blastocyst has established which 3 founding populations
Epiblast
Hypoblast
Trophoblast
What is embryo implantation
Attachment of the late blastocyst to the uterus
What kind of implantation do human embryos undergo
Interstitial implantation where the blastocyst penetrates the endometrial lining
Where does the amnion come from
What related structures are also formed from this
The epiblast specifies the amnion, forms the amniotic cavity and gives rise to a flat embryonic disc
What is Heuser’s Membrane
The secondary yolk sac, derived originally from the hypoblast
What does the trophoblast mediate
Invasion intro maternal tissue
What does the trophoblast diversify into
Cytotrophoblast (proliferative compartment)
Syncytiotrophoblast (multinucleate cells)
What forms lacunae
What is the role of these embryonic lacunae
Cavity formation in the syncytiotrophoblast
Embryo nutrition prior to development of the placenta
What did Wolpert say of Gastrulation
“It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life”
What are the 3 germ layers and when are they established
Ectoderm
Mesoderm
Endoderm
Established during gastrulation
Gastrulation is simply the formation of the 3 germ layers. True or false
False
Gastrulation also ensures correct positioning of the germ layers as a result of cell differentiation and relocation
When does Gastrulation occur
~day 14
What coordinates Gastrulation
Hypoblast
What happens to the epiblast cells of the embryonic disc in Gastrulation
They delaminate and migrate through the primitive streak in between epiblast and hypoblast
What does ectoderm give rise to
Epidermis and nervous system
What does the mesoderm give rise to
Muscle
Connective tissue
Bones
Circulatory system
What does the endoderm produce
Digestive system
Respiratory system
Internal organs
How many cells are in a morula
~128
What are the 2 sections of the blsatocyst
The inner cell mass and trophoectoderm
What are the fetal membranes
The amnion
Yolk sac
Allantois
Chorion
What is the amnion
A fluid filled sac surrounding the embryo, providing a protective aqueous environment for the developing foetus
What is the yolk sac
A highly vascular extra embryonic membrane
It provides the nutrient supply prior to the formation of the placenta
Where do the first blood cells originate
The yolk sac
What is the allantois
An extension the yolk sac into the connecting stalk to act as a source of embryonic blood cells
What is the chorion
The fetal component of the placenta
It is highly vascular for gas exchange, waste management, and nutrient transport during fetal growth
Are humans diploblastic or triploblastic
Triploblastic - human embryos have 3 germ layers
What is a diploblastic animal
Animals whose embryos have only 2 germ layers
Eg Hydra
What 2 germ layers do diploblastic animal embryos have
Ectoderm and endoderm
How is Gastrulation induced
Induced in the epiblast by the hypoblast through transmission of diffusible peptides
How does the embryo specialise
Inside out
When is the head tail axis of the embryo defined
Cell migration at the primitive streak
What have all embryos acquired by the end of Gastrulation
A body axis with a head and tail end
An inside out specialisation with 3 basic layers
A left right axis
What organises the main body axis
The node or primitive knot
What happens if you graft Hesen’s node from a quail embryo to a chick embryo
The chick embryo will have 2 axes: the host axis and the induced axis from the transplanted node
Discuss conjoined twins
Identical twins who develop with a single placenta from a single fertilised ovum
More common in females (3:1)
Mechanism responsible is probably a failure for twins to separate after Gastrulation (day 13)
How common are conjoined twins
1 in 40,000 but only 1 in 200,000
How is the embryonic endoderm formed
When does this occur
Hypoblast induces epiblast cells to undergo a an epithelial-mesenchymal transition.
These cells leave the primitive streak and invade the hypoblast, forming the definitive endoderm
Day 16
How is the mesoderm formed
After the formation of the endoderm, epiblast cells migrate into the space between the endoderm and the epiblast.
The mesoderm forms 5 separate layers.
How many layers does the mesoderm form?
What are they?
5
Cardiogenic mesoderm Axial mesoderm (AKA notochord) Paraxial mesoderm Intermediate mesoderm Lateral plate mesoderm
What happens once the endoderm and mesoderm are formed
Migration ceases and the epiblast becomes ectoderm
How does the notochord form
Days 19-21: there is invagination from the primitive node and axial cell migration
The notochord grows anteriorly
What does the formation of the notochord do
Determines longitudinal axis for the future differentiation of the vertebral body
Induces epiblast differentiation to become neural plate
Which part of the mesoderm is primarily involved in neurulation
When does this occur
Which to germ layers are involved
Notochord
Day 19 onward
Communication between mesoderm and ectoderm
Give evidence that the mesoderm induces neural tube formation in the ectoderm
Transplantation of a second notochord leads to a duplicate neural tube
Any ectoderm transplanted next to the notochord will be induced to form neural tissue
When do the anterior neural folds close
The later part of the 4th week
When does the posterior neuropore close
What becomes evident here
2 days after the anterior
An upper limb bud is evident
Give 2 defects caused by a failure of the neural tube to close
What are each caused by
Anencephaly - failure of anterior neuropore closure
Spina bifida - failure of posterior neuropore closure
What may cause defects in neural tube closure
How frequent are they
Folate deficiency
Valproate (drugs)
Cholesterol metabolism
1/300 - 1/5000
What does the neural crest develop
Schwann cells
Neuroglial cells
SNS
PNS
What does the neural tube form
Brain Neural pituitary Spinal cord Motor neurons Retina
What does the outer ectoderm form
Epidermis Hair Nails Teeth enamel Anterior pituitary
When do epiblast cells undergo transition to epithelial mesenchyme
What signals this
16 days
Underlying hypoblast
What layers does the lateral plate mesoderm divide into
Somatic
Visceral
4 facts about somites
Derived from paraxial mesoderm
Transient structures
Formed in pairs that flank to midline
Formed sequentially from cranial to caudal
When do somites begin to form
21 days
What is the clock and wavefront model
Describes somitogenesis in vertebrates
Mainly controlled by retinoic acid and FGF (these are antagonistic)
Every 90mins a new pair of Somites form
Negative feedback loop
What are the 3 types of somite
Myotome
Sclerotome
Dermatome
What do the myotome somites form
Epaxial (dorsal) and hypaxial (ventral) muscles of trunk and limbs
What does the sclerotome form
Axial skeleton, vertebrae and ribs
How are the vertebrae formed from somites
1 vertebra formed from 2 half sclerotomes on each side of the notochord
What disease spreads and shows a single dermatome
Zoster
Blistering in a single dermatome
What dictates a somite’s fate?
It’s cranial caudal position
Eg ribs will form from thoracic somites
Give experimental evidence that the fate of a somite depends on its position
If you transplant a somite from one region to another region it will grow structures appropriate to the original site
Which class of gene family controls correct axial specification of somites
What do these genes do
Hox
Give each segment an address/ specification
What happens if Hox expression is perturbed
Give an example/ evidence
Structures will form in the wrong place
Eg ribs can grow in lumbar and sacral vertebrae in Hox gene knockout mice
What is aristapedia
Hox gene mutation leading to flies having legs in the place of their antennae
What is the motif found in Hox genes
What does it do
The homeodomain
Activates or inhibits downstream genes concerning axis patterning, migration, cell death etc
Give an example of how Hox genes determine number and types of vertebrae in different animals
Hoxc -6
In chicks this determines that 7 vertebrae will develop into ribs
In snakes Hoxc-6 is expanded dramatically towards the head and towards the rear so there are many more vertebrae which develop ribs and lose limbs
How common are cervical ribs?
What might cause it
<1% live births
Spontaneous homoeotic mutation
How many Hox genes are implicated in human heritable diseases
> 27
Spinal nerve segmentation comes before somite organisation
True or false?
False
The segmental Organization of the spinal nerves is secondary to that of the somites
What does coelom mean
Cavity in Greek
What forms the thoracic cavity
Cranial folding
Where is the cardiogenic region originally
When
How does it move
Near the forebrain
In the flat embryonic disc
Cephalic growth displaces the cardiogenic region and is folded underneath, coming to lie on the ventral surface of the chest
How is the septum transversum first seen
Where does it move to during folding
As a thick bar of mesoderm between the cardiogenic region and the cranial margin of the embryonic disc
Lies between cardiac region and neck of yolk sac, separating thoracic and abdominal cavities
What does the septum transversum form
Part of the diaphragm
What innervates the diaphragm
Why is this not surprising
Cervical nerves (phrenic nerve: C3,4,5)
Septum transversum was originally adjacent to forebrain
What does the ventral folding of the embryo produce
Intraembryonic coelom lined with mesoderm
Intraembryonic coelom is lined with mesoderm. What does the mesoderm form?
The serous membranes (Parietal and visceral)
Where are the somatic and splanchnic mesoderm
What are their other names
What is the space between them called
Somatic (parietal) mesoderm: outer layer, beneath the ectoderm
Splanchnic (visceral) mesoderm: overlying the endoderm
Coelom
How does the dorsal mesentery form
Primitive gut tube hangs from the posterior body wall by a broad bar of mesentery
Below the septum transversum, the mesenteric bar thins out to form the more membranous dorsal mesentery That suspends the abdominal viscera in the coelomic cavity
Name 2 visceral organs that develop in the body wall
What group are these a part of
Why is this
Kidney
Bladder
Retroperitoneal organs
These organs are separated from the coelom by a covering of serous membrane
What separates the thoracic cavity
Pleuropericardial folds arise from the lateral body walls and grow medially towards each other separating developing lungs from the heart.
They meet and fuse forming the pericardial cavity and the pleural cavities (right and left)
How common are congenital pericardial defects
What does this involve
1/14000
3x more common in men
Persistent pleuropericardial foramen due to arrested development of pleuropericardial folds
What is the diaphragm formed from
4 structures Septum transversum Pleuroperitoneal membranes Muscular components of lateral body walls Dorsal mesentery of oesophagus
How common is congenital diaphragmatic hernia
What is it
How is it diagnosed
1/2000 to 1/5000
Failure of diaphragm to fuse allowing developing developing abdominal viscera to bulge into pleural cavity. If large enough this may stunt the lungs.
Using ultrasound
What is the usual cause of failure of diaphragm fusion
One of pleuroperitoneal membranes fails to meet septum transversum
How does a congenital diaphragmatic hernia present
Severe pulmonary hypoplasia and pulmonary hypertension
Scaphoid abdomen
Severely affected babies will be symptomatic after birth. Most will develop symptoms within 24 hours
What is a scaphoid abdomen
Boat shaped
Anterior abdominal wall is sunken and presents a concave contour
What induces lung development?
Prove it
Mesoderm
If cultured alone, a lung bud shows no further differentiation
If a lung bud is cultured with stomach mesoderm, gastric glands are formed
If the lung bud is cultured with intestinal mesenchyme, villi form
If developed with bronchial mesoderm, bud branches
If developed with tracheal mesoderm collagen forms but there is no branching
What is the respiratory diverticulum
When two tracheo oesophageal ridges start to separate the oesophagus from the lung bud
What happens to the lung bud after the respiratory diverticulum is formed
What happens to the tracheo-oesophageal ridges
Lung bud bifurcates into the precursors to the 2 bronchi and lungs
They fuse to divide the oesophagus from the trachea and the laryngo-tracheal endoderm becomes the lining of the trachea and the rest of the airway
What is TEF and how common is it
Tracheoesophageal fistula
OR
oesophageal atresia
Failure to separate trachea and oesophagus
Causes severe choking in neonatal baby
1/5000
Describe the signals that coordinate lung branching
FGF10 is secreted by mesoderm and guides bronchial branching
FGF10 induces new gene expression in the cells at the ends of the bronchial branches
SHH acts as negative feedback, inhibiting FGF10 expression locally. This stops outgrowth, promoting next round of branching.
How many live births are affected by congenital cardiovascular abnormalities
1%
What is the earliest functioning organ?
When does it begin to function?
The heart
Starts to beat at 22 days
When can the heart first start to propel fluid
24 days
What are the 4 structural shapes the heart goes through in development
Cardiac crescent
Linear heart tube
Looping heart
Remodelling heart
How are cardiac progenitors first recognisable
As a crescent shaped epithelium
How does the linear heart tube form
Heart progenitors move ventrally to form the linear heart tube, compromising an endothelial lining (endocardium) enveloped by a myocardial epithelium
How does blood flow through the linear heart tube
In flow caudal, outflow cranial
How does the linear heart tube form the looping heart
The tubular heart adopts a spiral shape. The inflow portion, including the common atrium, is forced dorsally and cranially so ends up above the developing ventricles
How is the heart remodelled after the looping heart stage
Heart divided into chambers by septation
This leaves distinct left and right ventricles and atria
How many sides of the heart tube has a thick layer of mesoderm
What does this become
3 sides
Myocardium
What is cardiac jelly
A gelatinous acellular matrix, secreted by the myocardium, separating the myocardium and endocardium
What are the primitive chambers of the heart
A series of bulges which form: Sinus venosus Primitive atrium Ventricle Bulbus cordis Truncus arteriosus
How does the linear heart pump
What prevents back flow
Where is blood expelled
Contractions begin at the sinus venosus (which acts as the pacemaker) and a wave of muscle contraction is propagated up the tubular heart
Cardiac jelly and constrictions
From the truncus arteriosus
When is the patterning of the heart initiated
How do we know this
During Gastrulation
In the linear heart the primitive atrium and ventricle have different cardiac myosin
What happens on day 23
The heart begins to elongate and fold and loop
What does looping of the heart do
Displaces bulbus Cordis inferiorly, ventrally and the right
Displaces primitive ventricle to the left
Displaces the primitive atrium posteriorly and superiorly
When is heart looping complete
By day 28
What forms the outflow regions of the ventricles
What about the actual ventricles
Superior end of Bulbus cordis
Inferior end of bulbus cordis forms most of right ventricle
Primitive ventricle forms most of left ventricle
Where does the base to apex heart axis point
What is it called when this is reversed
What is the name when all organs are swapped on the left-right axis
Left
Dextrocardia
Situs inversus
When does left right patterning begin
Elaborate
Gastrulation
The nodal gene is only transcribes in cells on the left side of the primitive streak
Where does our understanding of left right asymmetry come from
Studies of 2 mouse mutants
What is the inv mutation
What is nodal
In version of turning
Results in 100% reversal of looping
When nodal gene is transcribed on right side of primitive streak
What is inversus viscerum (iv)
Randomised left right orientation of the heart
Nodal is transcribed randomly on left or right
True or false:
The primitive atrium is v important for atrium formation
False
They mainly form the auricles
How do the definitive atria arise
What does this result in for the right?
Incorporation if the sinus horn (right atrium) and pulmonary veins (left atrium) to give the smooth walls of the atria
The SVC, IVC, and coronary sinus lie within the definitive right atrium
In the embryo, all venous flow enters which part of the heart
How do they get in
The right sinus horn (future right atrium)
Via the SVC and IVC
What does the left sinus horn give rise to
The coronary sinus
How does oxygenated blood enter the IVC
Via the ductus venosus in the liver
What is the first step in separating systematic and pulmonary circulations
Partial separation of the definitive atria and division of the common atrioventricular canal into right and left AV canals
How is the total separation of systemic and pulmonary circulations achieved in the embryo
IT DOESNT HAPPEN
V little blood flows through the foetal lungs and blood is shunted from right to left
How is foetal blood oxygenated
From the placenta, oxygenated blood enters the right atrium from the IVC and passes into the left atrium via the foramen ovale
What does the AV canal do initially
How is it remodelled
Connects the primitive atrium with the left ventricle
RV increases in size, pulling canal to the right
Tissue surrounding the canal thickens forming the endocardial cushions
Endocardial cushions grow towards each other, fusing to form the septum intermedium, separating the AV canal into the left and right canals
What do the left and right AV canals eventually form
The tricuspid and mitral openings
What induces endocardial cushion formation
Signals from the. Myocardium
When does the septum primum first form
What does it look like
What does it separate
Day 28
A thin membranous septum originating from the superior heart surface
Left and right atria
What happens to the heart in the 5th week
As the Septum primum approaches septum intermedium, the ostium primum is diminished
When is the ostium primum obliterated ?
This means blood can no longer travel from the foetal right atrium to the left atrium. True or false?
At the end of the 6th week
False: apoptosis occurs at the cranial end of the septum primum, forming the ostium secundum
Blood can always pass between the atria in the foetus
Describe the septum secundum
A second “fence”, this time thick and muscular that descends from the roof of the right atrium, to the right of the first fence
When does the septum secundum reach the septum intermedium?
It never quite reaches the septum intermedium and the remaining gap forms the foramen ovale
Is the blood in the foetal right atrium Oxy or deoxy
It receives both Oxy and and deoxy from the IVC and SVC
Describe the movement of blood through the foetal heart after the formation of the foramen ovale
The higher blood pressure in the right atrium pushes blood through the foramen ovale, easily pushing the flimsy septum primum open, into the left atrium to be pumped around the body
How does the foramen ovale close
Closes with the newborn baby’s first breath as the abrupt dilation of pulmonary vasculature and cessation of umbilical flow increase the blood pressure in the left atrium.
This increased pressure forces the septum primum against secundum, closing the foramen ovale
What causes atrial septal defect
AKA hole in the heart
If septum secundum is too short and the foramen ovale persists
How common is ASD
What happens in the heart
What are the symptoms
5-10% of babies congenital heart defects
Causes left to right shunting in newborn
Generally asymptomatic but persistent increased flow to RA leads to enlarged RV and pulmonary trunk, and eventually cardiac failure in later life
How is hole in the heart fixed?
When is surgery performed
Small holes can close spontaneously
Larger defects may require surgery to prevent complications
Between the ages of 3 and 5 years
How is the muscular ventricular septum formed
It grows from the inferior edge of the foetal ventricle after the 4th week towards the septum intermedium. This growth halts in the middle of the 7th week, leaving an opening between the ventricles that connects to the common outflow tract (truncus arteriosus)
When does the muscular ventricular septum begin to form?
Why does growth of the muscular ventricular septum halt in the 7th week
After the 4th week
Otherwise the LV would be shut off from the outflow tract
How is septation of the heart completed
2 spirals form on opposite sides of the inner surface of the truncus arteriosus
The ridges spiral and fuse at inferior edge of truncus arteriosus. This fusion spreads cranially and caudally, separating the outflow tract when the spiral septum fuses inferiorly with the septum intermedium and the muscular ventricular septum
What gives rise to the membranous ventricular septum
What does this form
When the spiral septum fuses with the muscular ventricular septum
The 2 separate ventricles
What is the most common congenital heart defect?
What causes this?
What can this defect lead to?
Ventricular septal defect (33%)
Failure of complete fusion of the spiral septum with the muscular ventricular septum and with the septum intermedium
Tetralogy of Fallot
How common is VSD
Which septum is it most common in
3/1000 live births
Membranous ventricular septum
How severe is VSD
How can it be treated
Severity depends on size and position of defect
Small defects close spontaneously in 50% of cases with no long term harm
A large VSD may damage heart or lungs as it causes heart to pump inefficiently by pumping oxygenated blood through the lungs repeatedly. This leads to pulmonary hypertension
Without surgical intervention, a large VSD can lead to congestive heart failure
What is the most common cyanotic congenital heart malformation
What causes it
Tetralogy of Fallot
1/1000 live births
Defect in spiral septum, which divides outflow tract into pulmonary trunk and aorta
What is the Tetralogy of Fallot
- Pulmonary stenosis
- Overriding aorta
- Large VSD
- Right ventricle hypertrophy
What is pulmonary stenosis
Pulmonary artery is too wide
What is an overriding aorta
Aorta too wide and shifted right so receives blood from right ventricle too
Why does hypertrophy occur in the Tetralogy of Fallot
The right ventricle has to work extra hard to pump blood up narrow pulmonary trunk
When is the tetralogy of Fallot surgically repaired
<1 year
Which 2 shunts allow blood to bypass the lungs
Foramen ovale
Ductus arteriosus
What does the ductus arteriosus allow
Shunts blood from pulmonary artery to aorta to by pass the lungs
How do the pulmonary vessels open at birth
What does this lead to
Pulmonary resistance drops
Closing of foramen ovale and ductus arteriosus
When do the first and second fences fuse
3 months after birth
What causes the ductus arteriosus to close
Reduced flow through it due to change in pulmonary circulation resistance
Reduced prostaglandin levels as maternal input is removed
What is a PDA
How common is it
When is it more common
Patent ductus arteriosus
10% of congenital heart diseases
In pregnancies with persistent perinatal hypoxaemia or maternal rubella or In babies born at high altitudes or born prematurely
What can we do to close a patent ductus arteriosus
Prostaglandin inhibitors
Surgery
Coil to seal it
Why can’t we use prostaglandin inhibitors for every case of PDA
Only effective in the first few weeks of life
It is most important for premature babies
How many patients with PDA die if it is not repaired
How do they die
1/3 by age of 40; 2/3 by the age of 60
Heart failure, pulmonary hypertension, endarteritis
What is endarteritis
Inflammation of inner arterial lining
How can you keep the ductus arteriosus patent
Why would we want to do this
Administration of prostaglandins
In babies with other cardiac abnormalities to keep them alive until corrective surgery
What does the arterial system look like originally
With paired aorta and symmetrical pharyngeal/aortic arch arteries
How does the venous system look originally
Paired cardinal veins, umbilical veins, and Vitelline veins
How do pharyngeal/ aortic arches develop
How many arches are there
Sequentially - the earliest ones regressing as later ones form
5 (I-VI) but V is not present in mammals
What does arch III form
Common carotid arteries
What forms the arch of the aorta
Arch IV
What forms the pulmonary trunk and the ductus arteriosus
Arch VI
How is the final aortic arch
Initial part: truncus arteriosus
Ascendant part: aortic sac
Transverse arch: from left IV pharyngeal/ aortic arch
Descending aorta: left dorsal arch
Which side contributes to the aorta?
What happens to the other side?
Left side
Right side structures regress or can be incorporated into other parts of the vascular system
How common is coarctation of the aorta
What is it associated with
3/10,000 births
~5% of congenital heart defects
Valve defects
What is coarctation of the aorta
What also is found if it is pre/ductal
What is found if it is post-ductal
Aortic lumen becomes significantly narrowed (from the Latin “coartare” - to press together)
Persistent ductus arteriosus
Circulation to distal body parts usually occurs through enlarged intercostals and internal thoracic arteries
What does coarctation of the aorta cause
High blood pressure in arms and upper body but low blood pressure in lower body and legs
How can you identify coarctation of the aorta
Different pulses in neck and groin and a distinctive heart murmur that can be heard through a stethoscope placed over the patient’s back
How is aortic coarctation repaired?
A small one can be removed and the two ends anastomosed
Large ones require bypass surgery
How common is aortic interruption
When is surgery required
1/10,000 births
1.3% of children with heart disease
1st year of life
What is Type B aortic interruption
Caused by obliteration of left VIth arch
For aortic interruption:
Where is Type A
Where is Type B
Where is Type C
A: distal to left subclavian artery
B: distal to left common carotid
C: distal to brachiocephalic artery
Why may there be an abnormal origin of the R subclavian artery
Where is the abnormal origin
What are the symptoms?
Abnormal obliteration of right VIth arch, leaving distal part of right dorsal aorta
Instead of ariseung with the right common carotid as the brachiocephalic artery, it rises as its own 4th branch from the aorta, after the left subclavian artery. It hooks back to reach the right side
Asymptomatic
Which organ greatly affects the vitelline and umbilical veins
Liver
What happens to the developing vitelline veins
A plexus forms between the left and right veins which is then surrounded by liver cords
This gives rise to the liver sinusoids
What happens to the left and right vitelline veins after a plexus forms between them
Left loses its connection to the heart and the anastomotic network develops into a single vessel: the portal vein
Right forms the hepatocardiac portion of the IVC
When does the ductus venosus form
What does it do
Forms with the hepatic sinusoids
Shunts blood from the placenta (via left umbilical vein) to the IVC
What happens to the umbilical veins
Left persists and anastomoses with the ductus venosus
Right is obliterated
When do the umbilical vein and ductus venosus close
After birth
The obliterated ductus venosus forms the ligamentum venosum
The obliterated umbilical vein is found in the lost margin of the falciform ligament
Congenital cardiovascular malformations accounts for how many of all congenital defects in live births and occur in how many of all live births?
20%
0.5-1% of all live births
Which gene is one of the earliest genes expressed in the cardiac lineage
Nkx2.5
What do you see in Nkx2.5 mutant mice
Absence of myosin light chain
What does Nkx2.5 encode
A homeodomain transcription factor that coordinates with zinc finger transcription factors of the GATA family to activate cardiac specific genes
When was Nkx2.5 first discovered to be required for normal heart development
How many mutations have been recorded to cause heart defects
In fruit flies
> 10
Both copies of the Nkx2.5 gene need to be mutated to cause disease
False
It is a dominant pattern of disease inheritance - only one mutation necessary
What do point mutations in Nkx2.5 cause
Can mutations in this gene affect adults
Atrial septal defects and AV conduction delays
Yes eg can cause progressive loss of AVN activity
What gene helps valve formation from the endocardial cushions
Notch1
Where do endocardial cushions form
What is this formation called
Where localised swellings of cardiac jelly become cellularised when endocardial cells delaminate in response to signals from the myocardium
Epithelial mesenchymal transition (EMT)
What are the reciprocal interactions involved in the EMT
Between the myocardium and endocardium
How do the endocardial cushions develop into valves
Which gene is required
Give evidence
They elongate to gradually form thin valve leaflets
Notch1
If Notch1 is blocked, cushions don’t form
What causes bicuspid atrial valve
Notch1 mutations (only 1 copy needs to be mutated)
Why might Notch1 mutations not become obvious until later in life
It is also important in preventing calcification of the valve
What causes Alagille syndrome
What are symptoms
Jagged 1 mutations
Pulmonary artery stenosis and Tetralogy of Fallot (jagged 1 mutations can lead to these individually, without Alagille syndrome)
What is Jagged 1
What does a mutation here cause
The ligand first the Notch receptor
Alagille syndrome: Pulmonary artery stenosis and Tetralogy of Fallot
True or false: the heart can regenerate before birth.
True but it loses this ability at birth
How can knowledge of heart development help treatment
Can be applied to derive cardiomyoctes from pluripotent stem cells
May also be possible to wake up dormant cardiomyocytes that are thought to exist within the heart
Which germ layer does the kidney develop from
Intermediate Mesoderm
What are the 3 stages of kidney development
Pronephros
Mesonephros
Metanephros
When does the urogential ridge begin to form
In which direction?
Week 4
Rostral caudal direction
When and where does the pronephos begin to develop
Is this structure essential for higher vertebrates
Day 24
Between somites 3-5 with the duct finding between somites 5-7
No it is a rudimentary structure but it is essential for embryonic survival of fish and amphibians
What happens to the pronephros once it is formed?
Degenerates v rapidly and is never. Functional in humans
What does mesonephros form
From day 28 and begins to regress at the cranial end at 5 weeks
How many nephrotomes does the mesonephros have?
What does it produce?
Never more than 30
Dilute urine
When does the ureteric bud form
Grows out of the mesonephric duct at 5 weeks
What induces formation of the metanephric kidney
The ureteric bud
How do the tubules in the mesonephros form
How many tubules are there
In cranio- caudal succession (cranial ones form first, then thoracic then abdominal)
Earlier ones degenerate as new ones form
30 tubules at any one time
What is an important function of the mesonephros
Production of weak urine which maintains the composition of the amniotic fluid
How do the metanephroi develop
Begins with 2 buds (the ureteric buds) which originate from the caudal end of the mesonephric duct.
These buds grow out unit the surrounding mesoderm and surrounding cells as the bud secretes signalling proteins
How do we know the ureteric buds signal induction in surrounding cells
If an artificial barrier is used to prevent proteins moving between cells, development stops
Define induction
Alteration of the fate of one cell type or tissue by interaction with a second
What are the 3 phases of induction
Initiation
Commitment to differentiation
Morphogenesis
Discuss the phases of induction in the example of metanephros development
Initiation: signals from the metanephrogenic mesenchyme induce growth of ureteric bud
Commitment: proliferation and differentiation of bud and mesenchyme (the response to the inducing signals)
Morphogenesis: in response to signals from the mesenchyme, the bud commenced branching morphogenesis and the mesenchyme responds by becoming epithelial in nature and forming nephrons
In short, what are the consequences of induction in mesonephros development
Ureteric branching morphogenesis
Epithelial morphogenesis
Describe the epithelial morphogenesis associated with metanephros development
Mesenchyme-epithelial transition is in response to Wnt expression
S shaped bodies form
thins on one side to form glomerulus
Fuses with ureteric bud tip
Extends to form proximal and distal tubules
What induces outgrowth of the ureteric bud
What does it grow towards
GDNF secreted From the metanephric mesenchyme (MM)
Grows towards the MM
What is GDNF
What does it bind to
Glial derived neurotrophic factor
Binds to Ret receptor on ureteric bud cells
How are the renal vesicles formed
The metanephric mesenchyme is induced by the ureteric bud to condense around the tips of the branching ureteric epithelium and undergo a mesenchyme to epithelial transition, forming renal vesicles
What triggers the mesenchyme-to-epithelial transition (MET)
Wnt9b from the ureteric tip upregulates FGF8 and Wnt4 production from the metanephric mesenchyme
This triggers (MET)
What do the following signalling proteins do in kidney development:
a) Wnt9b
b) FGF8
c) Wnt4
Where is each secreted from
a) up regulates FGF8 and Wnt4 (from ureteric bud)
b) stimulates proliferation of metanephrogenic mesenchyme (from MM)
c) regulates formation and differentiation of the comma and S shaped bodies to form renal vesicles (from MM)
What is the ampulla in the developing kidney
The growing tip of the branching bud
What follows induction at the ampulla during kidney ampulla
What is this called
What does it result in
Another branch grows out and one nephron forms
Dichotomous branching
The regular patterning of the kidney
What forms the collecting duct, the nephron and the convoluted tubules?
Collecting duct: from ureteric bud branches
The metanephrogenic mesenchyme form the nephron and convoluted tubules
When does the mean glomerular number level off in the embryo
Is this the final number?
36 weeks
No some nephrogenesis and functional maturation continues after birth
What processes form kidney blood vessels in the embryo
Smaller vessels are derived from vasculogenesis differentiated within the kidney
Large vessels are formed via angiogenesis- the invasion of the kidney by the renal arteries
How common is a development abnormality in the urinary tract
10% of all babies
However most don’t cause problems
When does kidney agenesis occur
If the ureteric bud does not reach / signal properly to the surrounding mesenchyme
What causes poly cystic or dysplastic kidneys
Tubules fail to form correctly
Cells may continue to proliferate
What probably causes double or bifurcated ureters
Defects in early stages of induction
Give the mean glomerular number at 3 points in life
15 weeks: 15,000
40 weeks: 740,000
Adult: 617,000
True or false:
Mean glomerular number decreases with age
True
Which other disease is a decline in glomerular number related to
According to whom
Give evidence
Risk of hypertension
Developmental Origins of Health and Disease
Genetically induced reduction in nephron number in mice is associated with increased blood pressure
What is nephron number in babies strongly associated with
Give a statistic
Birth weight
Babies with birthweight below 10th centile have 30% fewer nephrons
What is the Developmental programming hypothesis
That there is a relationship between low birthweight, nephron number and hypertension
How does the bladder form
The mesonephric duct and the ureteric bud both enter the posterior inferior aspect of the urogenital sinus.
In the males the mesonephric duct migrates inferiorly go enter the urethra as the vas deferens and in the female it regresses
The ureteric bud grows out and elongates you’re become the ureteric and the portion closest to the urogenital sinus splays out to generate the trigone
What is the trigone
Part of the posterior wall of the bladder
What is the urachus
What is its path
The connection between the developing bladder and the allantois
From the bladder to the umbilicus and the umbilical cord
What happens to the urachus after delivery
It fibroses to form the median umbilical ligament
What happens if the urachus fails to obliterate fully
A urachal fistula, cyst, or sinus may develop
A urachal fistula will result in urine leaking from the umbilicus
