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WEEK 24:
Embryology of limbs and clinical relevance:
| Question | Answer |
|---|---|
| initial growth and patterning of the limbs occurs when | during weeks 4-8 |
| appearance of limb buds | outpocketings at the end of week 4 (forelimb then hindlimb) |
| limb buds | mesenchymal core derived from lateral plate mesoderm (bones and connective tissue) with an ectodermal outer layer |
| ectodermal layer development | thickens distally and forms the apical ectodermal ridge (AER) |
| apical ectodermal ridge (AER) | has inductive influence that regulates the undifferentiation and differentiation of cells |
| cells closer to the AER | remain undifferentiated but rapidly proliferate |
| cells father away from AER | begin to differentiate into cartilage and muscle |
| how do limbs grow | proximo-distally |
| hand and footplates are formed as a result of what | limb bud flattening (WEEK 6) |
| first circular constriction | week 6- separates hand and foot plates from proximal segment |
| second circular constriction | week 8- separates proximal segments into two |
| where does apoptosis occur | at AER |
| further formation of digit formation depends on (3) | continued outgrowth of AER (inductive influence), core of mesenchyme turning into cartilage, and death of intervening tissues between digits |
| digits | fingers and toes (phalanges) |
| digits are initially interconnected by | tissue which then regresses via apoptosis to produce separate digits |
| apoptosis of interdigital tissue is dependent on | BMP signaling within the interdigital tissue under the influence of Shh from the zone of polarising activity (ZPA) |
| disruption of apoptosis of interdigital tissue can result in | syndactyly (which often affects digits 3,4, and/or 5) |
| cartilage formation involves | mesenchyme condenses and differentiates into chondrocytes where chondrocytes form the first hyaline cartilage models (week 6) needed for bone formation |
| what happens in the interzone | chondrogenesis ceased and becomes joint |
| endochondral ossification occurs when | starts by the end of week 8 |
| endochondral ossification process | mesenchyme condenses and differentiates into chondrocytes where chondrocytes form the first hyaline cartilage models and blood vessels invade the centre of diaphysis forming primary ossification centre (week 12) - bringing together osteoblast |
| secondary ossification centres are formed where and when | epiphyses after birth (growth continues as chondrocytes proliferate) |
| how many growth plates in long bones | 2 |
| how many growth plates in smaller bones (phalanges) | 1 - at the tip |
| primary ossification | occurs at week 12 where they bring together osteoblast (bone forming cells) and shove proliferating chondrocytes to epiphyseal ends |
| body musculature derived from | paraxial mesoderm (somites) |
| sclerotome | develops into vertebral and rib bones |
| myotome | develops into muscle |
| dermatome | develops into dermal connective tissue |
| myotome can further be divided into | primaxial (dorsomedial) and abaxial (ventrolateral) myotome |
| primaxial myotome (dorsomedial) | somite-derived cells only - affected by signaling factors from the neural tube to generate muscle precursors with limited migratory potential |
| abaxial myotome (ventrolateral) | respond to signals from adjacent lateral plate mesoderm to give rise to migratory population |
| limb bud elongation with migration of muscle cells includes | splitting into flexors and extensors, back muscles innervated by dorsal ramus, and body wall and limb muscles innervated by ventral ramus |
| limb rotation involves | dividing trunks and movement in both the upper and lower limb |
| trunk is divided into | segments that receive innervation from spinal nerves |
| distal ends of limbs flatten into | paddles- with the thumb and great toe most anterior and after flexure the elbow and knee lateral |
| limbs by week 7 | undergo torsion in opposite directions, upper limb rotates 90* laterally while lower limb rotates 90* medially |
| limb rotation in the lower limb | permanent pronation - which twists leg so that the foot faces downwards with great toe medial |
| dermatome | area of skin supplied by single spinal nerve which is evenly spaced horizontally in thorax and abdomen but more complex in upper and lower limbs |
| regulation of limb bud identity establishment involves (3) | paired like homeodomain transcription factor 1 (Pitx1), hindlimb-specific enhancer A/B (HLEA/B), and fibroblast growth factor 10 (Fgf10) |
| mechanism of regulation of limb bud identity establishment | |
| sonic hedgehod (SHH) and noggin found in | sclerotome |
| genes responsible for dermatome LOCATION ** | PAX3 regulated by NT-3 |
| genes responsible for DM muscle cells -> primaxial muscles | MYF5 regulated by WNT |
| genes responsible for VL muscles -> abaxial muscles | BMP4 and WNT regulates MyoD |
| PAX3 regulates | NT-3 |
| WNT regulates | MYF5 |
| BMP4 and WNT regulates | MyoD |
| patterning, growth, and maturation of the limbs occurs along | |
| proximo-distal growth and patterning S22 | |
| proximo-distal growth and patterning (S23) | |
| antero-posterior patterning (A-P patterning)^^ | established by zone of polarizing activity (ZPA) on the posterior side of limb (little finger side). SHH signaling from ZPA specifically signals formation of posterior elements |
| upregulation of ZPA signals results in | additional posterior elements (polydactyly on hypothenar side of hand) |
| duplication of ZPA results in | duplication of posterior elements (eg little fingers on both sides of thumb) |
| loss of ZPA results in | loss of posterior elements |
| dorso-ventral patterning | specifies dorsal surface (Extensors) vs ventral surface (flexors, palm/sole) of limbs |
| dorsal and ventral signaling factors | |
| SLIDE 25 | |
| limb defects - amelia | |
| limb defects - phocomelia | |
| limb defects - amniotic bonds | |
| limb defects - polydactyly | |
| limb defects - syndactyly | |
| limb defects - cleft foot | |
| transverse limb deficiencies | limb defects in which proximal structures are intact but structures distal to a transverse plane are partially or completely absent due to disruption of AER |
| osteogenesis imperfecta (brittle bones) |