The primordia of the limbs are called limbs buds, which appear as small elevations of the ventrolateral body wall during the 4th week of development. The upper limb buds appear in the lower cervical region on day 25, and the lower limb buds appear in the lower lumbar region on day 27. Each bud consists of an outer ectodermal covering and an inner mesenchymal core derived from the somatic mesoderm. A number of Hox genes* are expressed during the development of limbs (especially HoxB-8, HoxD-12 and HoxD-13).
*A gene that plays a central role in the final identity of a body region is called a ho-meotic gene. A cluster (group) of adjacent ho-meotic genes is called a homeobox (abbreviated as Hox). In human genome homeotic genes exist in four clusters titled Hox A, B, C, & D. Each cluster lies on a separate chromosome and the genes in each cluster are numbered 1 to 13.
Shortly after the formation of each limb bud, the mesenchymal core of the bud indus the ectoderm along the apex of the bud to become stratified to form a ridge-like thickening which is called apical ectodermal-ridge (AER). This ridge is an essential inductor in the limb development.
It is responsible for the elongation of the limb as well as for the progressive development of the mesenchymal parts of the limb. Due to the inductive influence of the apical ectodermal ridge, the mesenchymal cells subjacent to the ridge undergo rapid proliferation to form a progressive zone. As the limb bud grows, the mesenchymal cells located in the proximal part of the bud (ie, away form the AER) begin to differentiate into blood vessels, cartilage bone models, and muscles. In this way, the limb development
proceeds in a proximodistal direction. Patterning of the anteroposterior axis of the limb is regulated by a zone of polarizing activity (ZPA), which consists of a group of mesenchymal cells located at the posterior border of the limb near the flank. Patterning in limb development is well exemplified by the formation of the thumb preaxially and the little finger postaxially. It has been proved that the cells of ZPA produce vitamin A (retinoic acid), which initiates the secretion of a factor, called sonic hedgehog (SHH) that regulates the pattern formation in the developing limb.
Development of the limbs from the limb buds occurs during four week period from the 5th to the 8th week of intra-uterine life, the upper limbs developing slightly in advance of the lower limbs. The somatic mesoderm within each limb bud gives rise to mesen-chyme from which bones, tendons, ligaments, and vasculature of the limb develop. However, the local mesen-ehyme does not give rise to the limb muscles, which develop from the somatic mesoderm that migrates into the developing limb buds.
As the limb buds grow they become somewhat cylindrical in shape.However, very soon the distal end of each developing limb becomes flat-ftened and a constriction demarcates ifhis expanded, paddle-like portion from lihe proximal cylindrical segment of the iimb. In the developing upper limb the Herminal expanded parts are called md plates, whereas in the lower limbs these are known as foot plates.
Shortly after the formation of the hand and foot plates, the proximal cylindrical segment of the developing limb becomes divided into two parts by another constriction. The three divisions of each limb can now be recognized, ie, arm, forearm and hand in the upper limb, and thigh, leg and foot in the lower limb.
In each hand and foot plate five radial ridges, called digit rays, appear by the proliferation and condensation of the mesenchymal tissue within the plate. The digit rays are separated from each other by grooves. The tissue between the digit rays gradually breaks down and, thus, separate digits (thumb and fingers in the upper limb and toes in the lower limb) are produced by the end of the 8th week of development.