Limb Formation Flashcards
What does patterning require?
A local signalling centre
Limited repertoire of signalling molecules
When does development of the human limb bud take place?
Week 4s-8
What is patterning?
Creation of specific structures according to a pattern- in specific locations
Structure of limb bud
somatopleure- from lateral plate mesoderm. Hyaline cartilage model for endochondral ossification of bone
With an ectodermal epithelial covering- will form epidermis
How many axes of symmetry will the limb eventually contain? + what are they
3
proximodistal- near to far
dorsoventral- back to fron
anteroposterior- head to tail
What limbs develop first?
Hind limbs develop 1-2 days behind the upper
What enables limb outgrowth, and thus the proximodistal axes formation?
Apical Ectodermal Ridge
How is the AER formed?
FGF-10 formed by lateral plate mesoderm, induces AER formation-
causes the overlying ectoderm to thicken, forming the AER
Apical Ectodermal Ridge is formed at the tip of the limb bud, therefore enables elongation at the progress zone
What is the function of the progress zone?
The dividing cells release FGF growth factors to stimulate the AER to produce factors that encourage mitosis in the progress zone
What does the progress zone suggest about the formation of proximal structures?
Cells measure the time spent in the zone, and those staying a short time become more proximal structures
Evidence that Apical Ectodermal Ridge is important in limb formation
Knock out mouse formed- limb will not develop past the initial bud- truncation of distal structures
Explain dorso-ventral patterning
Wnt7a activity in the overlying ectoderm is restricted on dorsal side of the limb bud and En1 on ventral side
Experimental evidence for dorsoventral patterning
Knockout mouse without Wnt7a activity on both sides, formed a foot pad to develop from ventral side
Explain anteroposterior patterning
- determines the first digit side of the limb to the 5th digit side
- Shh is expressed in the caudal region of the limb but in the Zone of Polarising Activity
- expression of Wnt7a maintains expression of Shh
Explain ZPA role
Secretes Shh in only the posterior region of the limb
Experimental evidence for ZPA function
ZPA grafted onto anterior region of limb bud- forces a publication of limb structures
Morphogen definition
Chemical that produces different effects on cell fate at different concentrations
Example = Shh
How does polydactyly develop?
Mutations in Hoxa- or Hoxd clusters
Zone of polarising activity forms a new organiser region more anterior than the normal posterior one.
Secretes Shh in an abnormal region, which results in the development of extra digits
Digit formation stages
- Apical Ectodermal Ridge acts as a signalling centre
- AER persists locally- causing extension
- Other regions of the AER regress and degenerate due to the BMP signalling inhibiting FGF
- Apoptosis of the interdigital mesenchyme
What happens next in the development of the limb?
Long bone growth from lateral plate mesoderm-somatopleure
Explain stages of long bone growth
Week 12
- lateral plate mesoderm- somitic migrates into the limb bud and forms a condensation in the long axis
- chondrocytes then invade and secreted ECM to form a cartilaginous model of the bones
- ossification begins in the primary ossification centres
- endochondral ossification takes place, forming woven bone
- at birth the diaphysis is completely ossified but not the epiphysis
What may potentially inhibit early chondrogenesis?
Wnt6 signalling, secreted by overlying surface ectoderm
Origin of embryonic skeletal muscle
somite myotome- giving rise to myogenic progenitor cells
Explain initial structure of muscle in limbs
Limb level somites- hypxial lips of dermomyotome delaminate and migrate to the limb bud to form musculature or limbs
between limb somites- cells delaminate from the edges of the dermamyotome and form subjacent postmitotic myotome which gives rise to trunk muscles
