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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 at the end of week 4 | 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 which regulates what | 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 (make the digits and toes) |
| second circular constriction (week 8) | separates proximal segments into two (split into arm and forearm, thigh and leg) |
| 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 signalling 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 which form the first hyaline cartilage models (week 6) needed for bone formation |
| what happens in the interzone | chondrogenesis (formation of cartilage) ceased and becomes joint |
| endochondral ossification occurs when | end of week 8 |
| endochondral ossification process | mesenchyme condenses and differentiates into chondrocytes (cartilage models) -> blood vessels invade the centre of diaphysis forming primary ossification centre (week 12) -> secondary ossification centres form in epiphyses after birth |
| 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 (2) | primaxial (dorsomedial) and abaxial (ventrolateral) myotome |
| primaxial myotome (dorsomedial- located nearer to neural tube and back) | somite-derived cells only - affected by signalling factors from the neural tube to generate muscle precursors with limited migratory potential (dont move much) |
| abaxial myotome (ventrolateral- located towards limbs and body wall) | respond to signals from adjacent lateral plate mesoderm to give rise to migratory population (move away eg limbs) |
| limb bud elongation with migration of muscle cells includes (3) | 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) |
| key factors in the mechanism of regulation of limb bud identity establishment for hindlimb (3) | paired-like homeodomain transcription factor 1 (Pitx1) (determines it will be hindlimb), hindlimb specific enhancer AB HLEA/B (activates expression of hindlimb), and fibroblast growth factor 10/ Fgf10 (stimulate growth of hindlimb) |
| sonic hedgehog and NOGGIN signals | sclerotome formation |
| PAX3 (regulated by NT-3) signals | dermatome formation |
| MYF5 (regulated by WNT) signals | DM muscle cells to form primaxial muscles |
| BMP4 and WNT regulates | MyoD -> VL muscle cells -> abaxial muscles |
| patterning, growth, and maturation of the limbs occurs along (3) | proximo-distal, antero (rostral)- posterior (caudal), and dorso-ventral axes |
| antero-posterior patterning (A-P patterning) is established by^ | ZPA on the posterior side of the limb (pinky), where SHH signalling 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 (Wnt7) and ventral (engrailed-1) signalling factors are | antagonistic |
| amelia | absence of entire limb due to early loss of FGF signalling |
| meromelia | absence of part of limb due to later or partial loss of FGF signalling |
| phocomelia | short, poorly formed limb due to partial loss of FGF or HOX disruption |
| adactyly | absence of digits due to even later loss of FGF |
| ectrodactyly | lobster claw deformity (FGF variant of adactyly where middle digit is lost) |
| polydactyly | extra digits due to disruption of usually upregulation of Shh pathway |
| transverse limb deficiencies are | 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) | characterised by shortening, bowing and hypomineralisation of long bones in limbs (with increased risk of fractures/ severe lethal form in neonatal period) caused by dominant mutations in COL1A1/1A2 genes which produce type I collagen. |
| core of limb buds | mesenchymal core |
| the mesenchymal core of the limb buds are derived from | lateral plate mesoderm (bones and connective tissues) |
| outer layer of limb buds is made from which tissue | ectodermal |
| when does the limb bud flatten to form hand and footplates | week 6 |
| first circular constriction occurs at | week 6 |
| second circular constriction occurs at | week 8 |
| relationship between ZPA (zone of polarising activity) and Shh | ZPA releases Shh which influences BMP signalling within interdigital tissue to promote apoptosis of interdigital tissue |
| when do blood vessels invade centre of diaphysis forming primary ossification centre | week 12 |
| back muscles are innervated by | dorsal ramus |
| body wall and limb muscles are innervated by | ventral ramus |
| by week 7 the lower limb rotates | 90* medially |
| by week 7 the upper limb rotates | 90* laterally |
| spinal roots in upper limb | CT-T2 |
| spinal roots in lower limb | L1-S2 |
| limb outgrowth initated by | AER at the tip of the limb buds and proceeds from proximal to distal |
| what is formed first | proximal elements |
| FGF-10 | from lateral plate mesoderm, initiates limb bud outgrowth |
| BMPS | from ectoderm, induce formation of AER |
| RADICAL FRINGE | restricts AER to the distal end |
| SER-2 | induced by RF and establishes the border of AER |
| ENGRAILED-1 | assists the formation of the boarder of AER and repressed RF expression |
| FGF-4 and FGF-8 | maintain the undifferentiated zone (distal growth) |
| mesenchymal cells in the proximal end during proximo-distal growth and patterning no longer | are no longer under the inductive influence of AER of FGFs |
| differentiation begins under the influence of what for humerus/ femur | retinoic acid or MEIS1 |
| HOXA11 and HOXA13 (HOX genes) regulate what | radius/ulnar/tibia/fibula and caprals/metacarpals/tarsals/metatarsals/phalanges respectively |
| regulation of radius/ulnar/tibia/fibula and caprals/metacarpals/tarsals/metatarsals/phalanges respectively is regulated by | HOXA11 and HOXA13 (HOX genes) |
| BMPs in ventral ectoderm induce | EN1 (engrailed-1) which repressed WNT-7 and restricts it to the dorsal aspect |
| WNT-7 induces | LMX1 that specifies cells to be dorsal |
| syndactyly | fusion of digits due to BMP or Shh disruption |
Created by:
kablooey
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