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Updated: Jul 22 2022


Images bud.jpg
  • Limb Development
    • Overview
      • the appendicular system forms between the 4-8 weeks of gestation
      • limb bud development
        • appears to be under the control of fibroblast growth factors (FGF)
        • enlargement of the limb bud is due to the interaction between the apical ectodermal ridge (AER) and the mesodermal cells in the progress zone.
        • first identifiable by transvaginal ultrasound at 8 weeks
    • Steps of limb development
      • notochord expresses Shh
      • Shh regulates limb bud formation
        • limb bud is combination of lateral plate mesoderm and somatic mesoderm
        • growing outwards into ectoderm (called apical ectodermal ridge)
        • limb bud formed at embryonic stage 12 (26 days after fertilization)
      • mesenchyme condenses into preskeletal blastemal at core of limb bud
      • chondrification occurs where mesenchyme differentiates into chondrocytes
        • All upper limb bones are endochondral except distal parts of distal phalanges (membranous)
        • From proximal (humerus, 36 days after fertilization) to distal (distal phalanges, 50 days)
        • Factors required for chondrification
          • transcription factors – Sox-5, Sox-6, Sox-9
          • transforming growth factor superfamily – TGF-b, BMP-2
          • FGF family
            • receptor mutation leads to acrocephalosyndactyly (Apert syndrome)
            • patients with severe craniofacial features have mild hand syndactyly (gain of function in FGFR2c affinity for FGF2 expressed in craniofacial area )
            • patients with mild craniofacial features have severe hand syndactyly (loss of function in FGFR2c specificity for FGF2, and is now able to bind FGF10, more expressed in hands)
            • retinoids
            • hedgehog gene products
            • PTHrP
            • cadherins
            • WNT5a and WNT7a
      • Formation of joints requires repression of chondrogenesis at sites of future joints
        • proteins involved – WNT4, WNT14, growth and differentiation factor 5 (also known as cartilage-derived morphogenetic protein 1)
        • shoulder interzone appears at 36 days, hand interzones appear at 47 days
      • Finger separation
        • digital rays are evident within hand paddle at stage 17 (41 days)
        • interdigital mesenchyme cells undergo programmed cell death (stage 19 to 22)( days 47-54)
        • transcription factor Msx2 is expressed in interdigital mesenchyme, regulates BMP4-mediated programmed cell death pathway
        • transcription factor Hox-7 also expressed in interdigital zones
    • Limb patterning
      • Proximodistal 
        • first signaling center to appear is AER
          • controls proximal to distal growth
          • forms under FGF10 stimulation
        • removal /defect in AER results in proximal limb truncation
          • example is central deficiency (cleft hand)
          • another example is radial clubhand (radial dysplasia, absence of radius)
        • FGFs are the signaling molecule
          • FGFs expressed in AER include FGF4, FGF8, FGF9, and FGF 17
          • FGF8 expressed earliest and is obligatory for normal limb development
          • FGF4, 9 and 17 are redundant
          • disrupted FGF signalling leads to arrested limb development
      • Anteroposterior
        • second signaling center to appear is ZPA (zone of polarizing activity), along posterior limb bud
          • controls anteroposterior (radioulnar) limb growth
          • grafting ZPA on anterior limb margin leads to mirror-image digit duplication (ulnar dimelia, or mirror hand)
        • signaling molecule is Shh compound (dose dependent)
          • normal
            • high concentration of Shh on posterior (ulnar) side for small finger development
            • low concentration of Shh on anterior (radial) side for thumb development
          • posterior/ulnar side abnormalities
            • abnormal upregulation of Shh in the ZPA results in polydactly on the ulnar (posterior) side
              • extent of duplication is dose dependent (higher dose = more replication)
            • downregulation of Shh (on the posterior/ulnar side) leads to loss of ulnar digits
          • anterior/radial side abnormalities
            • abnormal upregulation of Shh in the anterior aspect of the limb bud (where Shh concentration is supposed to be low) leads to loss of thumb
          • timing
            • posterior elements (little finger/ulna) are formed EARLY prior to anterior elements which are formed LATE (radius/thumb)
            • disruption of AP patterning will result in loss of later forming elements (radius/thumb)
      • Dorsoventral axis
        • third signaling center is non-AER limb ectoderm /Wnt signalling center (progress zone, PZ)
        • dorsal limb ectoderm expresses WNT7a
          • activates Lmx1b (LIM-homeodomain factor) to regulate dorsal patterning
          • WNT7a is responsible for all dorsal features (including nails)
        • ventral ectoderm expresses en-1 (engrailed-1 protein, antagonistic to WNT7a)
          • inhibits WNT7a (and restricts it to dorsal ectoderm)
          • allows ventral limb development
    • Key Genes
      • Sonic Hedgehog (Shh) genes
        • secreted by ZPA
        • involved with HOX gene expression
        • anterior-posterior (radioulnar) growth
          • anterior (radial) mesoderm expresses ALX4
          • posterior (ulnar) mesoderm expresses Hox8
        • concentration gradient dictates formation of digits
          • little finger develops where there is highest Shh concentration
          • thumb develops where there is lowest Shh concentration
        • activates Gremlin
          • Gremlin inhibits BMPs that would otherwise block FGF expression in the AER
      • Hox genes
        • anterior-posterior (radioulnar) patterning
          • together with Shh
        • regulate somatization of the axial skeleton, essentially patterning digit formation
      • Wnt genes (Wnt7a)
        • expressed in dorsal (non-AER) ectoderm (Wnt signalling center)
        • dorsal-ventral growth
    • Mutations
      • removal of AER
        • truncated limb
      • duplication of ZPA
        • mirror-image duplication of the limb
        • Key Genes/Regions
        • Gene/Region
        • Expresses
        • Regulates
        • Apical ectodermal ridge (AER)
        • FGF8 is dominant (also FGF 4, 9, 17, which are redundant)
        • Proximal to distal growth and interdigital necrosis
        • Zone of polarizing activity (ZPA)
        • SHH
        • Anterior-posterior (radio-ulnar) growth
        • Non-AER limb ectoderm (dorsal)
        • Dorsal ectoderm expresses WNT7a, that activates Lmx1b (regulates dorsal patterning)
        • Dorso-ventral growth
        • Non-AER limb ectoderm (ventral)
        • Ventral ectoderm expresses en-1, antagonistic to WNT7a (regulates ventral patterning)
        • Dorso-ventral growth
  • Spine and Spinal Cord Development
    • Somites
      • the spinal column originates from pairs of mesodermal structures known as somites
      • somites develop in a cranial to caudal direction on either side of the notochord and neural tube
        • this process is dependent on the presence of the paraxis gene
      • somite layers
        • sclerotome
          • layer will become the vertebral bodies and annulus fibrosus
        • myotome
          • will lead to myoblasts
        • dermatome
          • becomes skin
    • Dorso-vental patterning
      • dorso-vental patterning of the neural tube determined by counteracting activities of
        • Sonic Hedgehog (Shh)
          • in the floor plate and notochord (ventral)
        • canonical Wnt/β-catenin
          • in the roof plate (dorsal)
    • Metameric shift phenomenon
      • the phenomenon of how the spinal nerves, which originally ran in the center of the sclerotome, exit between the two vertebral bodies at each level.
    • Progression
      • neural crest
        • forms PNS, pia mater, spinal ganglia, sympathetic trunk
      • neural tube
        • forms spinal cord
      • notochord
        • forms anterior vertebral bodies and nucleus pulposus
    • Ossification centers
      • vertebrae have 3 primary ossification centers
        • centrum (anterior vertebral body)
        • neural arch (posterior elements, pedicles, small portion of anterior vertebra)
        • costal element (anterior part of lateral mass, transverse process, or rib)
    • Intervertebral disc
      • nucleus pulposus forms from notochord
      • annulus fibrosus forms from sclerotome
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