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What do we currently know of the molecular control of limb development, and what remain the major gaps in our present understanding of this process?
Vertebrate embryonic limb development starts with the development of limb buds, which occurs in humans at day 24 for upper limb buds and around day 28 for the lower limb buds. Limb buds form as a bulge of mesodermal mesenchyme cells covered by ectodermal epithelium, the distal margin of which forms the apical ectodermal ridge (AER). Limb induction is the patterning process whereby the cells which form the limb bud are selected, and involves signalling between genes including Hox and GDF11, and areas such as the intermediate mesoderm (IM), somites, the organiser and lateral plate mesoderm (LPM). Each limb bud must grow along three axes, the dorsal-ventral (DV) axis, the cranial-caudal (CC) axis, and the proximal-distal (PD) axis. Limb bud growth is maintained by Fgf signals emitted from the AER. PD patterning is induced by signalling pathways including that of the Hox genes. The combination of these is responsible for growth of the stylopod, zeugopod and autopod regions of the limb. In the upper limb, these form, respectively, the upper arm containing the humerus, the forearm containing the radius and ulnar, and the wrist and hand. The lower limb is analogous. DV axis patterning depends on the positional interplay between signalling factors, primarily Wnt7a and Lmx1d. There is another signalling centre in the posterior mesoderm of the limb bud, the zone of polarising activity or ZPA, which is partially responsible for the CC axis and expresses Shh, Fgfs and the Bmp family. Finally, additional Shh, Gli3 and Bmp signals in the interdigital necrotic zone induce apoptosis to free digit rays from the digital plates. In limb induction, limb fields are specified from lateral plate mesoderm by a combinatorial Hox code. At the level of the limb buds, expression domains of genes Hoxc6, Hoxc8, and Hoxb5 have boundaries, which specify a CC axis. Mice lacking the Hoxb5 gene have an elevated shoulder girdle2. Studies of Hox genes in snakes where forelimbs do not develop, and of Hox expression domain shifts in mutant mice and chicks, confirm that limb bud field is specified by a certain combination of levels of Hox expressions in overlapping domains. However, the factors determining the boundaries of Hox gene expressions are not entirely elucidated. GDF11 is implicated as GDF11-deficient mice display posterior limb displacement and it seems to pattern the embryonic trunk CC axis; promyelocytic leukemia zinc finger protein may also regulate Hox expression2. Several signalling factors are involved in limb bud initiation: Fgf, T-box genes, retinoic acid (RA) and Wingless. Fgf-10 expressed by cells in the lateral plate mesoderm is known to initiate AER formation 8, however Fgf-8 is responsible for limiting Fgf-10 expression to only areas where limbs should develop 9; an Fgfsoaked bead will induce develop of an extra limb when applied to chick interlimb flank 1. Limb buds cannot develop in grafts which exclude somites, the organiser and the IM. These tissues express Fgf and other factors which could influence limb bud outgrowth and patterning, but exactly how they work is not known 2. Evidence for the importance of the AER maintaining limb bud growth until full length comes from experiments where premature removal of the AER results in truncated limbs. In experiments in chick embryos, the later the AER is removed from the elongating limb, the more developed along the PD axis the limb is. In cases where the AER is not maintained, such as in snakes, whales, chick wingless mutants and mouse limb deformity mutants, limb buds fail to develop.1 The AER stimulates outgrowth by expressing Fgf; these signals have been shown to partially rescue limb bud development where the AER has been removed. 2
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