Overview
This lecture covers the embryological development of limbs, including structures involved, stages of limb formation, genetic regulation, and common limb abnormalities.
Appendicular Skeleton and Limb Buds
- The appendicular skeleton consists of limbs and their girdles (shoulder, pelvic).
- Limbs begin as limb buds from the lateral body wall at the end of the 4th embryonic week.
- Forelimb buds appear first, followed by hindlimb buds (1-2 days later).
- Limb buds have a mesenchymal core from lateral plate mesoderm, covered by ectoderm.
Formation and Differentiation of Limb Structures
- The apical ectodermal ridge (AER) forms at the distal bud and induces limb growth.
- Limb development proceeds from proximal to distal: stylopod (humerus/femur), zeugopod (radius-ulna/tibia-fibula), and autopod (hand/foot elements).
- Flattening of terminal parts creates hand and foot plates by week 6, with digit separation via apoptosis.
- Limb rotation occurs at week 7: upper limbs rotate laterally, lower limbs medially.
Cartilage, Bone, and Joint Formation
- Central mesenchyme condenses and differentiates into chondrocytes, forming hyaline cartilage.
- Endochondral ossification (cartilage to bone) starts by the end of the embryonic period.
- Primary ossification centers develop in long bone shafts by week 12.
- At birth, diaphysis is ossified; epiphyses remain cartilaginous until after birth.
- Joint structures form alongside cartilage and bone development.
Muscle Development and Nerve Supply
- Limb muscles derive from ventrolateral somite cells.
- Upper limb muscles are supplied by nerves from lower cervical and upper thoracic regions; lower limbs by lumbar and sacral segments.
Molecular Regulation of Limb Development
- Limb positioning: Hox (homeobox) genes, especially HOXB8.
- Upper limb specification: TBX5; lower limb: TBX4.
- AER maintenance: fibroblast growth factors (FGF4, FGF8).
- Patterning: Sonic Hedgehog (SHH) gene for anterior-posterior axis, MSX2, and others.
- Stylopod, zeugopod, and autopod segment identities regulated by specific HOXA genes.
Clinical Correlates: Limb Abnormalities
- Limb defects are common and classified by extent and nature of absence or malformation.
- Amelia: complete absence; phocomelia: absence of long bones with distal rudimentary parts.
- Brachydactyly: short digits; syndactyly: fused digits; polydactyly: extra digits; ectrodactyly: missing digits.
- Genetic associations: HOXA13, HOXD13, TBX5 (Holt-Oram syndrome).
- Osteogenesis imperfecta: collagen gene defects cause bone fragility and blue sclera.
- Marfan syndrome: mutation in fibrillin gene (chromosome 15) causes long limbs, arachnodactyly.
- Arthrogryposis: multiple joint contractures, often neurological in origin.
- Clubfoot and congenital hip dislocation result from abnormal structural development or fetal position.
- Amniotic bands can cause limb constrictions or amputations.
Key Terms & Definitions
- Appendicular skeleton — bones of the limbs and girdles.
- Limb bud — early protrusion from embryonic body wall that forms limbs.
- Apical ectodermal ridge (AER) — ridge at bud tip critical for limb elongation.
- Stylopod — proximal limb segment (humerus/femur).
- Zeugopod — middle limb segment (radius/ulna or tibia/fibula).
- Autopod — distal limb segment (hand/foot).
- Endochondral ossification — process where cartilage turns to bone.
- Amelia — complete limb absence.
- Phocomelia — hands/feet attached close to trunk, absent long bones.
- Brachydactyly — short fingers/toes.
- Syndactyly — fused fingers/toes.
- Polydactyly — extra fingers/toes.
- Ectrodactyly — missing fingers/toes.
Action Items / Next Steps
- Review key gene functions (HOX, TBX5, TBX4, FGF, SHH) in limb development.
- Memorize types and definitions of limb abnormalities.
- Prepare diagrams of limb bud stages and rotations for study.
- Read next chapter on skeletal system development.