Limbs Development

The development of the limbs start approximately at the end of the fourth week, ( moore p410), the exact trigger for limb development is not fully understood, it is believed due to the effect of homeobox-containing (Hox) genes complex. (Langman) hox genes determine the location of the limbs in the cranio-caudal axis of the body. ( human embryology and the developmental biology)p217, mention that at the beginning the hox genes cluster trigger the expression of the Tbx5 in the region of the future upper limbs and Txb4 in the future lower limbs regions, (human embryology and developmental biology) also mention Pitx-1 as a crucial factor in the appearance of the lower limbs. (Longman) limb growth induced by fibroblast growth factor 10 (FGF10) which is secreted by the lateral plat mesoderm at the regions of limbs formation. (achieving bilateral symmetry) Tbx5 in conjunction with Wnt2b factor govern the expression of FGF-10 in the lateral plate mesoderm (13,14). As a result of these expressions (essential of human embryology moore) limb bud formed due to the condensation of the growing cells in the somatic mesoderm, as these cells increase in number the limb elongate externally forming the limb bud, (mooore p 410) the limb bud growth occur at the ventrolateral wall of the body, this collection of mesenchymal cells lying underneath a layer of ectoderm. By the day 26 or 27, upper limb buds start to be apparent, and one or two days later, the lower limb buds become obvious. ( moore ) due to the development of the cranial part of the embryo, the upper limb buds appear low in the trunk, when the upper limb buds appear at the level of caudal cervical segments, the lower limb buds are opposite the lumber and cranial sacral segments. Now the limb bud is formed from a core of mesenchymal cells covered from outside with a layer of ectoderm. The ectoderm and mesodermal cells then will arrange in groups to secret molecules and signals that interact with each other promoting the organisation and the growth of the limb.

( human embryology p70) in the early stages the surface ectoderm become thicker all over the limb bud, later only the ectoderm at he apex of the bud undergo thickness and forming what is called apical ectodermal ridge (AER) , ( the human embryology and developmental biology p 217) , therefore the ectoderm become differentiated into ventral ectoderm, dorsal ectoderm and the AER as a border between them, ( human embryology and developmental biology) FGF-8 produced from the ectoderm in the lateral side of the early bud is responsible for AER formation. On the other hand the mesoderm in the early stages of the limb development is consist of undifferentiated cells implanted in loos network of collagen fibres and ground substance, later different regions in the mesenchyme are recognized, (moore p410) at this stage limb mesenchym is of two types, that close to the AER is formed of undifferentiated rapidly increasing cells , ( Longman ) call it progress region, ( moorep410) mention another collection of mesenchymal cells at the posterior margin of the limb bud called zone of polarized activity (ZPA).

It can be seen now that the limb bud is formed of ectodermal outer layer which divided into ventral, dorsal ectoderms and thicker layer of ectoderm intervening them, the AER. In the same manner the mesoderm core is composed of the progress zone and the ZPA. The next section will illustrate the molecules and signals secreted by each of this layers and their effect on each other and on the pattern of limb development and growth, and the possible anomalies if an interruption in this process occur.

(Langman)when the AER is determined, it secrets endogenous fibroblast growth factors (FGFs) the FGF-4 and FGF-8, (human embryology and developmental biology) mention that FGF-8 produced in the whole length of the AER, while FGF-4 secreted only in its posterior part, (langman) these factors keep the cells in the progress region in proliferating, undifferentiated phase. ( moore) this bring about the proximal-distal evolution of the limbs. (moore) in addition FGFs trigger the ZPA resulting in expression of sonic Hodgehog (Shh) gene, the latter is believed to preside over the anterior-posterior formation of the limb.( moore) another two factors expressed from the epidermis of the limbs are the Wnt-7 from the dorsum ectoderm and Engrailed-1 (EN-1) from the ventral ectoderm of the limb bud, these factors are associated in determining the dorsal-ventral axis of the limb. The radical fringe expressed in the dorsal ectoderm of the limb causes expression of SER2 in the edge between the ectoderm in the dorsal and ventral aspects of the limb, due to the SER2 action the AER is limited to the distal tip. The radical fringe is clogged from expression in the ventral ectoderm as a result of the effect of EN-1 factor, ( human embryology & developmental ) the Wnt-7 produced by the dorsal ectoderm trigger the mesenchyme close to it to express Lmx-1b, ( moore) the Lmx-1b control the doral-ventral formation of the limb, (human embryology) the Wnt-7 is inhibited from production in the ventral ectoderm as a result of the action of the En-1, therefore Lmx-1b does not expressed in the ventral side of the limb. As mentioned previously the proliferated, undifferentiated state of the progress region is a result of the FGF-4 and FGF-8 action, ( human embryology) the progress region express Msx-1 gene, ( langman ) later, because of the limb growth, the AER migrate more distally from the cells in the proximal component of the progress region, thus the effect of AER on this region reduced leading to conclude of these cells,( moore) because of that these mesenchymal cells differentiated into blood vessels and bone shaped cartilages. We mentioned earlier that the FGFs have an effect on the ZPA leading to its growth and expression of Shh, (langman ) additionally ZPA secrets retinoic acid which activate the secreted Shh, the activated Shh control the arrangement of the limb in the anterior- posterior axis. ( langman ) the location of the ZPA in the forelimb is influenced by Hoxb-8, which in turn believed to be expressed by the effect of the retinoic acid. ( moore) thus the endogenous retinoic acids also participating in the growth and formation of the limb.(moore) interestingly a signal from Shh and Wnt-7 preserve the AER. ( human embryology) at the same time ZPA is created, a series of homeobox-containing genes, the Hoxd-9 to Hoxd-10 in the limb are expressed as a result of Shh action, where Gli-3 is restrict the expression Hox genes to the posterior portion of the limb bud, Shh express Gremlin molecule, this molecule has two inhibitory effects, it inhibits the effect of the bone morphogenic protein-2(BMP-2), the BMP-2 is an inhibitor to the FGF-4 of the AER, thus the Shh keep the action of FGF-4 which in turn influence the ZPA to secret the Shh, the other inhibitory effect of the Gremlin molecule ,which is located on the posterior aspect of the limb, is on the effect of Gli-3, hence the action of the Gli-3 limited to the anterior side, that to obstruct the expression of Shh. ( essential embryology) in the fifth week, the peripheral end of the limb bud smooth out to form the hand and food plates. (human embryology 217) as a result of limb bud elongation the ZPA become located more distally, and as a consequence of ZPA derived Shh producing cells condensation around the ZPA, the ZPA become isolated from the effect of AER, for this reason the ZPA does not participate in the digits development, and also this isolation result in the cessation of limb growth.( langman) hox genes complex are controlling bone shape formation.( Moore 410) by the end of the fifth week chondrofication centres start to exist, and by the end of the sixth week limb skeleton is completely cartilaginous, in the seventh week osteogenesis of the long bones starts at the primary ossification centres in the middle of the cartilaginous skeleton, then by the week twelve, the primary ossification centres appear in the entire long bones, (langman ) later, other ossification centres are revealed at the end( epiphyses) of particular bones, these are the secondary centres. (moore410) when the hand and food plates have been formed in the fifth week, the week after the digital rays are formed in the hand plate as a result of mesenchymal tissue condensation, these digital rays will give rise to the fingers, during the seventh week, similar condensation occur in the food foot plates, this will form toes. The mesenchyme in the digital rays is developed into mesenchymal primordial of the bones in the digits due to the effect of the AER at the tip of the digital rays, whereas the mesenchyme between these rays of loose kind that shortly after disappear leaving notches between the digital rays, by the end of the eighth week it is completely broken-down, this process of tissue breakdown is a consequence of programmed cell death(apoptosis), which believed to be enhanced by BMPs, these are molecules of TGFB superfamily. (Human embryology 2170) BMP-2, BMP-4 and BMP-7 in addition to Msx-1and Msx-2 factors are expressed in the digital spaces, therefore the programmed cell death is strongly associated with these factors, likewise, FGFs play a major role in this process by influencing do opposite effects, while FGF-2 prevents the BMPs action, the FGFs enhance the formation of Msx-2. (moore410) when the long bones are created, myoblasts collected to be the muscles of the limb bud, the myoblasts are differentiated from the myogenic precursor cells that had migrated from the dermatome regions of the somites. During its development the limbs undergo several movements and rotation. (developmental anatomy Arey) as the peripheral end of the limbs flattened, contraction just proximal to it occur separating it from the more proximal cylindrical part, afterward, another coartication occur dividing the cylindrical portion into two parts. Along their development, the limbs alter their position in relation to the body, firstly, they face caudally ( life before birth 2nd ) in the fifth week when the hand developing it faces towards the trunk, (developing anatomy Arey) then they move away from the body wall, in the following stage, the limbs flex ventrally at the elbow and the knee, thus, the knee and the elbow directed externally, leaving the thumb and the big toe on the cranial side of the limbs, eventually both limbs rotate 90 degree on their long axis, (moore ) where the upper limbs rotate laterally, the lower limbs rotate in the reverse direction,(life before birth 2nd) dorsal elbow of the elbow to 90 degree occur in weeks 7-9, as a consequence, the elbows pointing downward, while the knees upward.

Anomalies of limbs development

(shh-independed regulation) GLI-3 protein mediates the action of Shh in the limb development, it important in specifying the bone shape and in determines the number of the digits and their character, mutation in Gli-3 results in asymmetry of the extrimeties with two phalanges in the digit ( litingung et. al; te welscher et. al., 2002b) polydactyly may also occur(hill et.al., 2007). (abnormal antroposterior) deficiency in the retinoic acid reduce the activity of Shh, and decrease the expression of the BMP-2 and FGF-4 and FGF-8, on the other hand, it increases the activity of Hoxb-8, as a consequence, the developed limbs are distinctly small(rudimentary) , and relatively in anterior position, and occasionally even not undeveloped( name) (startford et. al.,1996). (Genetic of limb anomalies) absence of FGF-10, does not interfere with clavicle formation, but the remaining parts of the limb can not develop, this called complete truncation, mutation in the genes responsible for FGFs formation causes chondrodysplasia, interruption of Tbx5 expression, leads to Holt-Oram syndrome (22,23) ( include hypoplastic, absent or triphalangeal thumb, agenesis or hypogenesis of the radius . Hoxa-13 inactivation results in synpolydactyly (38,39) ( associated of mesoaxial poly and syndactyly, and may be associated with numerous carpal, metacarpal and phalanges anomalies). (why study human limb malformatios), mutation in the gene Lmx1b causes nail-patella syndrome ( clough et. al., (1999)), FGFR2 (fibroblast growth factor receptor 2) mutation results in Apert syndrome, with syndactyly (Hajihosseini et, al (2001) , mutation of the Hoxd-13 leads to synpolydactly or syndactyly type II featured by soft tissue adhesion between the third and fourth fingers and between the fourth and fifth toes(11,12). ( mutation in the BMP4 date 3/3) decrease in the BMP4 causes syndactyly of the digits and in some cases polysyndyctaly. ( human embryology ) Hoxd13 mutation leads to syndactyly, insertional polydactyly and brachydactyly. ( langman ) polydactyly of the middle finger is believed to be a consequence of Shh misexpression.

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