Limb Development

Limb development in tetrapods — animals with four limbs — is an area of active research in developmental biology. Limb formation begins in the limb field, as mesenchymal cells from the lateral plate mesoderm proliferate to the point that they cause the ectoderm above to bulge out, which is known as the limb bud. Fibroblast growth factor (FGF) induces formation of an organizer, called the apical ectodermal ridge (AER), which guides further development and controls cell death. Apoptosis — programmed cell death — is necessary to eliminate webbing between digits.

The limb field is a region specified by expression of certain homeobox (Hox) genes and Tbx genes; Tbx5 for forelimb and Tbx4 for hindlimb. Establishment of the limb field requires retinoic acid signaling in the developing trunk of the embryo from which the limb emerges.

Limb formation results from series of epithelial-mesenchymal inductions between the mesenchymal cells of the lateral plate mesoderm and the overlying ectodermal cells. Cells from the lateral plate mesoderm and the myotome migrate to the limb field and proliferate to create the limb bud. The lateral plate cells produce the cartilaginous and skeletal portions of the limb while the myotome cells produce the muscle components. The lateral plate mesodermal cells secrete a fibroblast growth factor (FGF7 and FGF10, presumably) to induce the overlying ectoderm to form an important organizing structure called the apical ectodermal ridge (AER). The AER reciprocatively secretes FGF8 and FGF4 which maintains the FGF10 signal and induces proliferation in the mesoderm. The position of FGF10 expression is regulated by Wnt8c in the hindlimb and Wnt2b in the forelimb. The forelimb and the hindlimb are specified by their position along the anterior/posterior axis and possibly by two T-box containing transcription factors: Tbx5 and Tbx4, respectively.

Programmed cell death removes the "webbing" between the digits and joints. BMP signaling induces cell death and Noggin blocks cell death in the digits.