Limb Development - Anatomy & Physiology

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Introduction

The limbs develop from the lateral plate mesoderm. Limb development is highly conserved; in all land vertebrates there are only four limbs and they are always opposite each other with respect to the midline of the body. All vertebrate limbs have the same patterning of; stylopod - proximal part of the limb which produces the humerus or femur; zeugopod - intermediate part of the limb which produces the radius and ulna or tibia and fibula; autopod - distal part of the limb that produces the carpals and metacarpals or tarsals and metatarsals. Other animals also follow this limb pattern including the greatly modified bird's wing.

Limb Bud Formation

• The limbs begin as lateral proliferations of the mesenchymal lateral plate mesoderm covered by ectoderm.
  • The lateral plate mesoderm proliferates in a lateral direction along the entire midline, but then stops at the region of the interlimb (area between the limbs).
  • This produces small buds, which will continue to grow to eventually form the limbs.
• Proliferation of the lateral plate mesoderm cannot sustain entire limb growth; instead the apical ectodermal ridge (AER) maintains growth.
  • The AER develops as mesenchymal cells in the distal limb ectoderm that has locally thickened by changing their morphology from cuboidal to columnar.
  • It divides the limb into dorsal and ventral halves.
  • The ridge can be seen when looking at the limb bud in a distal to poximal direction.
• The AER maintains an area of rapidly proliferating cells beneath it, called the progress zone (PZ).
• The rapidly increasing number of cells drives the limb bud out distally, elongating the limb.
• As cells leave the PZ they differentiate.

Patterning of the Limb

Proximal - Distal Patterning

• Governed by the PZ.
• The first cells to leave the PZ have a proximal identity.
• These cells have been in the PZ for a shorter amount of time than those that leave the PZ last, which have a distal identity.
• "Identity" is achieved by the HOX - A gene expression.
  • Cells that leave the PZ early have fewer HOX - A genes expressed than those which leave later.
  • Less HOX - A gene expression results in a more proximal cell appearance.

Anterior - Posterior Patterning

• Important in producing the correct number of digits of the correct morphology.
• An area of mesenchyme exists adjacent to the AER, in the posterior of the distal limb called the zone of polarising activity (ZPA).
• The ZPA produces a morphogen(substance that induces other cells to change).
  • This morphogen works in a dose - dependant manner.
  • The morphogen diffuses to form a concentration gradient and has different effects on cells depending on it's concentration.
  • Higher concentrations of this morphogen produces posterior digits.
    • Posterior digits have more cells than anterior cells.
    • The more cells, the more morphogen produced.
    • The more morphogen, the more posterior the digits.
• Polydactly is common in animals, and is due to defects in the ZPA.

Dorsal - Ventral Patterning

• Important for the proper development of both internal and external structures:

Internal - muscle and bone

External - hair, nails, footpads

• This requires control over the ectoderm and mesoderm.
• It is the ectoderm which controls dorsal - ventral patterning.
  • It achieves this by coordination of it's own patterning with the underlying mesoderm i.e. dorsal ectoderm gives rise to dorsal mesoderm.
• Dorsal - ventral patterning controls the positioning of the AER as it exists at the boundary of the dorsal and ventral aspects.