Abstract
Over the last 15 years, great improvements in genetic engineering and genetic manipulation strategies have led to significant advances in the understanding of the genetics governing embryological limb development. This field of science continues to develop, and the complex genetic interactions and signalling pathways are still not fully understood. In this review we will discuss the roles of the principle genes involved in the three-dimensional patterning of the developing limb and will discuss how errors in these signalling cascades correlate to congenital limb deformity in humans. This review is aimed at orthopaedic surgeons wishing to understand the principles of congenital limb deformity related to genetic signalling errors. It is by no means a comprehensive study of the molecular genetics governing the complex interactions involved in each step of limb development. There are however many syndromes involving limb deformity for which the molecular causes are unknown.
Highlights
The genetic processes that control development of the limb, in both vertebrates and invertebrates, are complicated and are still not fully understood
An understanding of the complex temporal and spatial co-ordination of genetically driven molecular pathways in the developing limb is crucial to understanding the pathology of congenital limb deformity
In the future a complete understanding of the pathways and pathology involved in embryological human limb development may lead to the development of molecular genetic therapies that may prevent or improve these disabling abnormalities
Summary
The genetic processes that control development of the limb, in both vertebrates and invertebrates, are complicated and are still not fully understood. Several gene families are involved in the spatially and temporally co-ordinated growth and differentiation of the developing limb bud The products of these genes act as signals to turn on other ‘‘downstream’’ genetic pathways. Areas where the limb buds will develop, specific Hox genes become upregulated by retinoic acid This initiates downstream genetic signalling, ensuring synchronised and progressive growth along the three axes of growth: anterio-posterior, dorso-ventral and proximodistal. On the initiation of limb outgrowth other transcription factors are expressed to control specific areas of patterning, i.e. forelimb versus hindlimb. For instance ectopically expressed Tbx can induce expression of the forelimb marker Hoxd and repress the hindlimb marker Hoxc9 [1, 2] The important role these trancription factors plays is highlighted in experiments where Tbx is knocked out or inactivated. Fgf signals the ectoderm to induce Fgf, which is instrumental in the formation of the apical ectodermal ridge (AER)—a thickened area of pseudo-stratified columnar epithelium at
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