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Describe limb development from embryo to adolescence Human limb development takes place between approximately day 24 and day 56. The 2 upper and 2 lower limbs are formed in a similar sequence of events (which occur earlier for the upper limb) from ectodermal and mesodermal tissue. The bones, ligaments and tendons originate in the lateral plate mesoderm, the muscle and endothelial cells in the somites (segmented paraxial mesoderm), and the Schwann cells and melanocytes are formed from migratory neural crest cells. The first stage in limb development is the formation of limb buds which first appear as outgrowths from the ventrolateral body wall at the end of week four. The upper limb bud appears in the lower cervical region on the 24 th day whereas the lower limb appears slightly later in the lumbar region at around the 28 th day. Both the upper and lower limb buds are formed by the proliferation of the somatopleuric lateral plate mesoderm in the limb regions of the flank and consist of an ectodermal covering and an inner mesodermal core which consists of mesenchymal cells that eventually become the bones and the connective tissues of the limb. As the limb buds form, the underlying somatopleuric mesoderm release signalling molecules and these induce the formation of the apical ectodermal ridge which is a ridge like structure along the apex of the ectoderm (as seen in diagram above). This structure plays a key role in the outgrowth of the limb buds and this was shown when surgical removal of the ridge resulted in the truncation of distal limbs. The apical ectodermal ridge expresses many types of fibroblast growth factors and it is these proteins which cause the outgrowth of the limb mesenchyme. The action of fibroblast growth factor was shown when beads that were soaked in this growth factor led to the formation of another limb between the fore and hind limb when inserted into the flank of a chick embryo. The idea that the fibroblast growth factor causes the outgrowth of limbs was further supported when a knockout for the gene for the FGF receptor in an embryo led to the inhibition of limb development. The formation and the external shape of limbs rely on the positioning of the mesenchymal mesodermal cells in the following three axes: proximal-distal, craniocaudal and dorsoventral. The relative positioning of the cells in these three axes is crucial as it determines the identity of the cells. The first axis is the proximal distal axis which controls the order of limb segments; in the upper limb the order is arm, forearm, wrist, hand whereas in the lower limb the order is girdle, thigh, leg, ankle and foot. The key structure involved in the formation of this axis is the progress zone which is the region containing proliferating mesodermal cells. This zone is formed by the fibroblast growth factors released by the apical ectodermal ridge which trigger the proliferation of mesenchymal cells at the distal end of the limb. The amount of time the mesenchymal cells remain in the progress zone,
therefore under the direct influence of the apical ectodermal ridge, determines the cells position on the proximodistal axis. Cells that exit the progress zone after a short time, therefore receive little influence from the apical ectodermal ridge, form the proximal structures such as the humerus on the upper limb whereas cells that remain in the progress zone for a long time differentiate to form distal segments of the limb such as the phalanges. This concept of the relative time spent in the progress zone determining the proximodistal axis was shown with transplantation experiments using chick wing buds. When an artificial bud was formed by inserting a late formed mesenchyme to an ectodermal cap of any age it resulted in only the formation of distal structures. However if a mesodermal core of a young wing bud was inserted into the same ectodermal cap it led to the formation of a whole limb bud. The identity of the structures along the proximal distal axis is determined by the expression HOX genes. These genes are expressed in overlapping patterns along the proximal distal axis within the growing bud and it is the combination of the specific HOX genes that determine the identity of segments along the axis. For example the arm is formed as a result of the combined expression of HOXD9 and HOXD10, whereas the humerus is formed as a result of the combined expression of the genes HOX9,10 and 11. The role of HOX genes in proximodistal differentiation was shown experimentally when a double knockout of the HOXA11 gene resulted in the complete absence of the ulna and radius. The absence of certain HOX genes also leads to various clinical disorders. A mutation in HOXA13 leads to the hand foot genital syndrome where there is the fusion of carpal bones and of small short digits. The craniocaudal axis results in the differentiation from the first digit side of the limb to the fifth digit side. This axis is regulated by a morphogen gradient and this was shown using chick wing buds. When a caudal edge of the wing bud was inserted to the cranial edge of the another wing bud it resulted in the cranial half of the wing bud forming digits that were a mirror image of the normal digits on the caudal half of the wing bud. This result showed that the caudal edge of the wing bud, which contains the zone of polarising activity (see diagram below), produced a morphagen which diffused to form a concentration gradient across the wing bud. The concentrations found at specific locations determine which digits are induced. In the chick it was shown that a high morphogen concentration induced digit four whereas sequentially lower concentrations led to the formation of digits three and two. Likewise in a developing human embryo, a group of cells located on the posterior border of the limb adjacent to the flank forms the region known as the zone of polarising activity. In this region the cells produce retinoic acid and this initiates the expression of sonic hedgehog. As the limb grows outwards, the zone of polarising activity shifts distally where it remains close to the apical ectodermal ridge. The sonic hedgehog expressed forms proteins 'Gli-3' and it is the concentration gradient of these transcription factors that determine digit formation. Misexpression of retinoic acid in the anterior margin of limb which contains a normally expressing zone of polarising activity in the posterior border leads to duplication of structures which are a mirror image of each other.
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