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Limb Development (Limb patterning (While external shape is being…

- - - - Proximal ossifies quickly -> little growth
      - Distal ossifies during puberty -> induce growth
      - Growth of long bone maintained by proliferation of chondrocytes in growth plates
      - Achondroplasia: defects in cartilage proliferation at growth plate -> premature closure of plate and shorted limb bones
    - - Digits forms when cell death in the AER separates plate into five parts
      - Digits continue to grow and cell death in intervening mesenchymal tissue delineates the digits
    - - proximodistal growth: Shoulder to fingers and hips to toes
        
        Regulated by AER (FGFs)
        
        loss of AER (e.g. amniotic banding clip off -> look at kidneys - mesoderm, as produce amniotic fluid) or FGF signalling -> failure to develop limb
      - Anteroposterior (or craniocaudal): thumb to pinky and big toe to little toe
        
        Zone of polarizing activity (ZPA) establishes caudal (posterior), making a pinky (and ring finger)
        
        ZPA produces retinoic acid and shh (sonic hedgehog)
        
        shh is a cholesterol and thus cannot migrate far (stays localised)
        
        factors secreted by ZPA indirectly induce proliferation at AER
        
        shh signals to Gremlin to form FGF-4 and stimulate limb growth, once developed enough, former shh cells die and form a layer that blocks signals from shh cells to Gremlin, ceasing limb growth
        
        Removing wedge of former shh producing cells can induce growth again
        
        formation of digits
        
        Balance of cell proliferation at AER and cell death in intrdigital regions where AER regresses
        
        Syndactyly: fusion of fingers due to inadequate cell death
        
        Polysyndactyly: duplication of digits (very often posterior, ie. pinky)
      - dorsoventral: dorsum (top of palm/ foot) to palm/sole
      - Bone identity regulated by HOX genes
        
        proximo-distal patterning of limb bones
      - At tip of limb bud is the apical ectodermal ridge (AER), signals to mesenchyme to proliferate and limb grows
        
        Removal inhibits outgrowth (arrest at current stage, can happen through amniotic banding and cutting AER), transplantation of second AER duplicates limb
      - mesoderm controls limb identity (depends on where mesoderm is derived from), nonlimb mesoderm does not allow limb development
      - Maturation of limb elements
        
        Sequence: proximo-distal and postero-anterior (ulna (caudal) before radius (nearer to thumb) (cranial))
  - - - amelia: absence of entire limb
      - Meromelia: absence of part of limb
      - Phocomelia: short, poorly formed limb
        
        Multifactorial: FGF disruption, HOX disruption , angiogenesis disruption (not enough blood supply to build bones)
    - - Ectrodactyly: lobster claw deformity (middle digit lost)
      - Adactyly: absence of digits
      - Polydactyly: extra digits
      - Syndactyly: fusion of digits
- - - - Unknown etiology, but often associated with subclavian artery anamolies (cause ischemia during time of pectoralis muscle development, affect angiogenesis)
    - - Ventral body wall absent, hard to deal with as need to use muscle flaps to supply strength for body wall
    - - Proper joint/ skeleton development requires force feedback from muscles