The Involvment of the Hox Genes in
Limb Development

     It is known that limb identity occurs at stage 10-11, yet Tbx4 and Tbx5 expression only occurs later at stage 12, implying the use of other signals. It was shown by Logan et al (1998) and Johnson and Tabin (1997) that the expression of the Hox genes precedes that of the T-Box genes and Pitx1, suggesting that the Hox code may play a role in selecting those genes for expression. In other words, the Hox genes act as early coordinating signals, providing positional cues to developing limb bud cells, upon which Tbx4 and Tbx5 act upon to form legs and wings, respectively.

     A certain group of Hox genes, the HoxD cluster are first seen to be expressed around the posterior of the limb bud; they can be endogenously influenced by Shh and FGF's, although the exact mannor of which is still unclear. The HoxD gene expression pattern is quite dynamic and goes through several stages of expression, with a set of early HoxD genes being expressed in the forearm and lower leg at an early developmental stage, and again at a later stage in the hand and wrist, ankle and foot (Johnson and Tabin 1997). Therefore, the phenomenon 'posterior prevalence' rings true in limb development with the more 5' genes of the cluster exerting a more dominant effect over downstream genes. Thus, different individual members of the Hox code have different effects on differentiation.

     Thus, as putforth by Johnson and Tabin (1997), the primary mode of the Hox genes is to regulate and influence limb patterning at different stages of development, including proliferation of undifferentiated mesenchyme cells and organization and condensation of the mesenchyme into cartilage.