Development of the Limbs Flashcards
What are HOX genes?
A group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of ‘position’, ensuring that the correct structures form in the correct places of the body.
By what week are the limbs well differentiated?
Week 8
What germ layer do the limbs come from?
Lateral plate mesoderm (bone, skeletal muscles, some organs, blood vessels)
What is mesoderm?
The mesoderm is one of the three germinal layers that appears in the third week of embryonic development. It is formed through a process called gastrulation.
What are the 3 components of mesoderm?
- Paraxial mesoderm
- Intermediate mesoderm
- Lateral plate mesoderm
What does the paraxial mesoderm give rise to?
Paraxial mesoderm forms somites that give rise to the cells that form the vertebrae and ribs, the dermis of the dorsal skin, the skeletal muscles of the back, and the skeletal muscles of the body wall and limbs
What does the lateral plate mesoderm give rise to?
Limb skeleton and connective tissues
What do the somites then divide into?
- A ventral part - the sclerotome
- A dorsolateral part - the dermomyotome
What does the sclerotome give rise to?
Vertebral column
What does the dermomyotome then divide into?
A dermatome and a myotome
What does the dermatome go on to form?
Dermis of the skin
What does the myotome go on to form?
Skeletal muscles
The myotome then subdivides into a dorsal and a ventral part. What does the dorsal part give rise to? What does the ventral part give rise to?
Dorsal part –> gives rise to the muscles of the back
Ventral part –> gives rise to the muscles of the limbs, thoracic and abdominal walls
What will the muscles of the back be innervated by?
Dorsal rami of spinal nerves
What will the muscles of the limbs, thoracic and abdominal walls (ventral myotome) be innervated by?
Ventral rami of spinal nerves
How do the limbs initially appear?
Appear as limb buds in week 4
What are limb buds?
Outpouchings from the ventrolateral body wall
What does ‘hindlimb’ refer to? ‘Forelimb’?
Hindlimb - lower limb
Forelimb - upper limb
Does the hindlimb bud or the forelimb bud develop first?
Forelimb, by a couple of days
What are the limb buds composed of?
- Initially the buds consist of a core of tissue derived from the lateral plate mesoderm
- This will form connective tissue and bone
- This is covered by a layer of ectoderm
What does the lateral plate mesoderm core of the limb bud then differentiate to form?
The bones and connective tissues of the limbs
The mesoderm of the somites (the myotome) then begins to migrate. Where does it migrate?
Either ventrally or dorsally
As the ventral myotome migrates, what are its 2 destinations?
- Anteriorly
- Limb buds
As the myotome migrates, some migrates anteriorly. What does this give rise to?
Anterior body wall muscles
Regarding the myotome that migrates into the limb bud, what does this give rise to?
Skeletal muscles of the limbs (upper and lower)
As the mesoderm (myotome) from the somites migrates into the limb buds, what does it take with it?
Ventral rami of the spinal nerves
Where does the dorsal part of the myotome migrate? What do they take with them?
Dorsally to form the back muscles. They take with them the dorsal rami of spinal nerves.
Once the somite mesoderm enters the limb bud, what does it condense into?
A posterior and an anterior condensation
What does the posterior condensation become?
- The extensors and supinators of the upper limb
- The extensors and abductors of the lower limb
What does the anterior condensation give rise to?
- The flexors and pronators of the upper limb
- The flexors and adductors of the lower limb
What are the upper limb buds innervated by?
The ventral primary rami of spinal nerves C5-T1 (brachial plexus)
What are the lower limb buds innervated by?
The ventral primary rami of spinal nerves L1-S3 (lumbosacral plexus)
The extensors of the upper limb lie posteriorly but the extensors of the knee lie anteriorly. What embryological action can explain this?
Limb rotation
In what direction does the upper limb rotate?
Laterally
In what direction does the lower limb rotate?
Medially
Where are the flexors and extensors of the upper limb found?
Flexors: anteriorly
Extensors: posteriorly
Where are the flexors and extensors of the lower limb found?
Flexors: posteriorly (hamstrings)
Extensors: anteriorly (quads)
What are the 3 limbs that limbs develop along?
- Proximodistal
- Craniocaudal
- Dorsoventral
Describe proximodistal patterning
Allows limbs to get longer; shoulder > hand, hip > foot
Describe craniocaudal patterning
Thumb (most cranial) > little finger (most caudal)
Describe dorsoventral patterning
Back of hand/foot looks very different to palm of hand/foot
What is proximodistal outgrowth responsible for?
Lengthening the limb
What does the mesenchymal core of the bud secrete? What does this induce?
Initiates proximodistal outgrowth
- Mesenchymal core of the bud secretes a fibroblast growth factor 10 (FGF10)
- FGF10 induces thickening of the overlying ectoderm along the tip of the limb bud - the apical ectodermal ridge (AER)
What induces the thickening of the apical ectodermal ridge (AER)?
FGF10
Once the AER has formed, what does it secrete? What is the result of this?
Expresses FGFs 4 and 8 –> rapid proliferation of cells underlying the AER – the progress zone.
What is the result of this rapid proliferation of cells underlying the AER?
Proximodistal outgrowth –> lengthening of limb bud
What is the progress zone?
Region of rapid cell proliferation underneath the AER
What can disruption of the AER affect?
Halts proximodistal outgrowth
What is Amelia? How does it occur?
- AER has been disrupted early
- Early failure of FGF signalling/AER
- Complete absence of an entire limb
What is Meromelia? How does it occur?
- Partial absence of one or more limb structures.
- Later or partial loss of FGF signalling/AER function
- Arrest of outgrowth (terminal part of limb hasn’t formed)
- Vascular abnormalities may also be responsible.
Segments of the AER may also fail. What is a cleft (‘split’) hand/foot caused by?
Failure of the middle of the AER to form properly
What are FGFs?
The fibroblast growth factor (FGF) family is one of the largest growth factor families
What is the result of ectopic FGF?
Can cause abnormalities such as supernumerary limbs
What does craniocaudal patterning explain?
Explains why the thumb is lateral and the little finger is medial
What determines craniocaudal patterning?
Determined by a region of mesenchyme in the caudal part of the limb bud – the zone of polarising activity (ZPA)
What is the primary responsibility of the ZPA?
The AER itself is maintained by the Zone of Polarising Activity (ZPA) which is found in the posterior base of the limb bud
What is the secondary responsibility of the ZPA?
To ensure asymmetry in the limbs.
What does ZPA secrete? What is the result of this?
- ZPA in caudal part of the bud secretes SHH (sonic hedgehog)
- High concentration of SHH in the caudal region induces caudal structures e.g. little finger
- SHH diffuses from the ZPA in a cranial direction.
- Ring, middle and index develop under progressively lower levels of SHH
- Low concentration cranially induces cranial structures e.g. thumb.
Are high concentrations of SHH found caudally or cranially?
Caudally
Which fingers develop under progressively lower levels of SHH?
Ring, middle and index
Which fingers develop under low conc of SHH?
Thumb
What can ectopic ZPA at the limb bud lead to?
Mirror image duplication; may explain some cases of polydactyly (extra digts)
What does dorsoventral patterning explain?
Why ventral and dorsal sides of hands/feet look different (e.g. nails)
What does the dorsal ectoderm express that drives dorsoventral patterning?
Dorsal ectoderm expresses Wnt7 > activates the gene LMX1 > LMX1 specifies development of dorsal structures
What does the ventral ectoderm express that drives dorsoventral patterning?
Ventral ectoderm expresses Engrailed-1 > this inhibits Wnt7 > so dorsal structures cannot develop > allows development of ventral structures
What is Nail Patella syndrome?
A rare condition affecting the nails, bones, kidneys and eyes. The defect is in the LMX1B gene. (example of defect in dorsoventral patterning).
How do the digits start to form?
- Distal part of the limb buds flatten to form hand and foot plates in week 6
- Apoptosis in the AER splits it into 5 segments
- Continued PD outgrowth in 5 segments under AER to form and lengthen digits
- Apoptosis between the digits separates them
What is Syndactyly?
fusion of digits, which occurs due to a lack of apoptosis between the digits during development.
What is Polydactyly?
increased number of digits
What are the causes of limb abnormalities?
- Genetics – hereditary or spontaneous mutations
- Drugs – ‘teratogens’ – examples?
- Environmental toxins / poisons – examples?
- Maternal illness
- Amniotic band syndrome
- Unknown / unidentifiable causes in many cases
What is Phocomelia?
- Digits develop prematurely
- Proximal elements of limb absent
What can cause Phocomelia?
Can be due to genetic factors or teratogens – most commonly associated with thalidomide use by mothers during pregnancy – a drug that was marketed as an antiemetic (for morning sickness)
What does thalidomide inhibit?
Inhibits expression of FGF 10 and 8; also thought to inhibit angiogenesis (the development of blood vessels).
