In human development, each limb results from a developmental field. The developmental fields are determined during gastrulation. These limb fields are established by the expression of HOX genes. The expression of the factor Tbx-5 causes the limb to develop into a hind limb, and expression of Tbx-4 causes the limb to develop into a forelimb. Beginning from the fourth week from fertilization, over a period of 25 days, a complex of genetic signals control the intricate pathways that result in a limb with the correct orientation, size, and number of digits. Limb development is a continuous process divided into four stages: the bud stage (initial outgrowth), the paddle stage (dorsoventral flattening), the plate stage (relative expansion of the distal end), and rotation stage (rotation around the proximodistal axis).
The limbs of the embryo develop from buds that protrude from the side of the main body axis. Limb buds arise on the lateral body at the level of sclerotomes as ectoderm and mesoderm (somite) proliferations. In particular, each limb bud consists of a mesenchymal core of mesoderm covered by an ectodermic cap. Limb buds will become the early arms and legs of the embryo. The upper limbs appear before the lower limbs that are delayed about two days in respect to the upper limbs. At the early stages of embryonic development, the forelimb and hind limb buds look like paddles on either side of the embryo and are indistinguishable from one another. The limb buds continue their formation by the migration and proliferation of the differentiating mesenchymal tissues. The ectoderm at the tip of the bud thickens to form a specialized structure, called the apical ectodermal ridge. This structure is the signaling center that allows proper growth along the proximodistal axis (shoulders to digits). Concomitantly, the limb becomes flattened along the dorsoventral axis (back of hand to palm) and asymmetric along the anteroposterior axis (thumb to little finger). Proximodistal, dorsoventral, and anteroposterior axes represent the routes of the normal limb growth. The most proximal structure (stylopod) begins to differentiate first, followed by the progressive differentiation of more distal structures (zeugopod and autopod). This outgrowth and patterning depends on the establishment and maintenance of other signaling centers within the limb bud, named the zone of polarizing activity located in the mesenchyme at the posterior margin of the bud, and the non ridge ectoderm of the bud. These developmental components are interdependent and, through a series of reciprocal signals and feedback systems, yield the correct tissue patterning and growth. Each bud develops to form a complex of interconnected limb elements comprised of bone, muscle, and tendon characteristic of either the fore limb or hind limb. The actual trigger for limb bud initiation is still unknown, although likely candidates have been identified as Fibroblast Growth Factor 8 and 10.
The plate stage is characterized by the formation of flattened plate-like areas on the distal ends of the limbs called the hand plates and foot plates They are flattened along the dorsoventral axis. Within these distal plates, some structure is noticeable. There are radially arranged thickenings called digital rays (precursors of the digits). Between the digital rays are thin areas where cells begin to undergo apoptosis (programmed cell death) that allow the separating of the digits. The thin areas are called interdigital grooves. This arrangement gives rise to free digits. A constriction on the limb just proximal to the hand and footplates, called primary constrictions of the limb, is evident in this stage. These constrictions will develop into wrists and ankles. At approximately seven weeks, the longitudinal axes of the upper and lower limb buds are parallel.
In the rotation stage, the position of the limb buds relative to the trunk change is a predetermined manner not related to muscle activity or inherent osseous torsion. During this stage, the rotation of the limbs creates a three dimensional structure. Because of the differentiate growth of the cartilage model that continue to elongate the limb, different parts grow at different rates. This causes a twisting or rotation of each limb around its proximodistal axis. Upper limbs rotate one way (laterally or externally), while lower limbs rotate the other way (medially or internally) bringing the great toe to the midline from its initial postaxial position. This creates the characteristic positions of the limbs with the point of the elbow facing caudally and dorsally, and the knee facing cranially and ventrally. Consequently, the equivalent bones and muscles of the upper and lower limbs are oriented 180 degrees apart. This means that in the structural organization of the upper and lower limbs, their flexors and extensors are positioned on opposite sides and the movements at equivalent joints are in opposite directions.
The skeleton of the limb arises from somatic mesoderm by means of endochondral ossification. Formation of the intermediate segment (forearm) involves programmed apoptosis to separate a single mesenchymal condensation into two cartilage models (one for the radius and one for the ulna). In addition, separation of the digits, as previously mentioned, depends on apoptosis within the interdigital grooves. Cartilage breaks down to form the joints in specific points. Periosteum, ligaments, tendons, and intramuscular connective tissues form from the non-condensed mesenchyme. In addition to somatic mesoderm, there are cells that migrate into the limb bud from the body wall. These cells are identified into three groups: (1) somitic components (somitic myotomes in particular) that migrate into the limb buds and give rise to all of the musculature of the limb, (2) spinal nerves from the brachial plexus that go to the upper limb and from the lumbosacral plexus that go to the lower limb, and (3) blood vessel precursors going into the limb to provide the vasculature.
By the end of the eighth week, the limb is perfectly formed. From there on out, the only remaining development is growth that is synchronized with that of the fetal body.
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