Genetic regulation of embryological limb development with relation to congenital limb deformity in humans

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.

Fig. 1

The role of T-box genes in limb identity: chick embryo study demonstrating the distribution of expression of Tbx5 (upper limb), Tbx4 (lower limb) and Pitx1 (lower limb) reproduced with permission of the Company of Biologists [34]

Fig. 2

Tri-phalangeal “indicised” thumb typical of Holt–Oram syndrome (due to Tbx5 mutation)

Fig. 3

a Stylopod stage: expression patterns of Hox genes during formation of the humerus. b Zeugopod stage: overlapping expression of Hox genes pattern the developing radius and ulna. c Autopod stage: patterned Hox gene expression governs the structural identity of the developing hand

Fig. 4

Synpolydactyly: examples of limb abnormalities caused by mutations in HOXD13

Fig. 5

The developing limb bud showing relative positions of the zone of polarising activity, the apical ectodermal ridge and the progress zone