Proximal to distal differentiation (PD) of the growing limb bud occurs by a precise and dynamic interaction between the underlying mesoderm and overlying ectoderm. The mesoderm stimulates the overlying ectoderm to form a layer of pseudostratified cells called the Apical Ectodermal Ridge (AER). The role of mesoderm in determining site-specific patterning is confirmed by transplanting chick leg mesoderm to the wing area: toes develop at the end of the wing. Similarly, the necessity for the AER layer is shown by its removal. This prevents limb formation; grafting of the AER to ectopic sites stimulates additional digits.
Once the AER has formed, it stimulates mesenchymal cells beneath to form a proliferating layer called the Progress Zone (PZ). The AER prevents cells within the PZ from differentiating by secreting a morphogen, thought to be fibroblast growth factor (FGF) isoforms 2, 4 and 8. FGF diffuses back to the PZ to stimulate proliferation, but when the mesodermal cells have been displaced from the most proximal end of the PZ, they are no longer exposed to its influence. This allows cells to begin differentation. Cells which leave the PZ early differentiate into more proximal structures whereas those leaving later are sequentially more distal in terms of differentiation.
The influence of FGF isoforms can be implied from exogenous application to flank somitic mesoderm in animal models leading to:
On a molecular level, FGF activates the gene Msx-1 which encodes a transcription factor within the PZ. Msx-1 then influences the expression of Hox genes within the PZ. Indeed, the exact order of Hox gene expression can be used to identify the specificity of patterning within the developing limb bud. Hox genes are activated in an overlapping series of domains temporally and spatially. They can influence gene expression by direct DNA binding. Also, they are under the simultaneous influence of morphogens specifying other axes such as the sonic hedgehog gene (Shh) product which is involved in antero-posterior (AP) patterning.
Abnormalities of proximal to distal patterning may result in transverse deficiencies such as amelia and symbrachydactyly. Abnormalities of PD and AP patterning can lead to intercalated deficiencies and phocomelia.
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