Kostakopoulou, Konstadina; (1996) The role of the gene Msx-1 in limb development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In developing vertebrate limb buds, pattern specification occurs in the distal region known as progress zone. The progress zone is a region of mesenchymal cells influenced by an interaction with the apical ectodermal ridge that is proposed to maintain cells in a positionally labile, undifferentiated and proliferative state. The aim of this research was to investigate the function of the Msx-1 gene, which is expressed at the progress zone and is correlated with outgrowth. Msx-1 expression in the progress zone is maintained by apical ridge signals and as the bud grows out and cells leave the progress zone, they switch off Msx-1 expression and differentiate into cartilage and other tissues. To test the hypothesis that Msx-1 is involved in maintaining the characteristics of progress zone cells, recombinant retroviruses were prepared encoding Msx-1. When chick limb buds were infected with the viruses in ovo by grafting vims-infected cells to the buds there was no effect on limb development, even though northern hybridisation and immunocytochemistry showed that the viruses directed synthesis of correctly processed chicken Msx-1 mRNA and Msx-1 protein. Similarly, there was no effect on the behaviour of cultured limb bud mesenchyme cells. These results suggest that Msx-1 act in concert with other factors to maintain progress zone characteristics. The ability of chick limb bud stumps to regenerate distal structures when FGF-4 was applied was investigated systematically. When amputations were made within 600?m of the tip and FGF-4 applied to the posterior part of the bud or both apically and posteriorly, outgrowth of stump tissues occurred and a virtually complete skeleton, muscle and nerve pattern developed. Regeneration of distal structures was correlated with re-activation of Msx-1 and by means of Dil injection experiment, the Msx-1 expressing region was found to correspond to the region from which cells were recruited into the new outgrowth. In addition, the regeneration potential of chick limb buds stumps was also correlated with Shh and Hoxd-13 expression. At proximal amputation levels where FGF-4 did not lead to regeneration neither Msx-1 nor Shh expression was induced. These results are consistent with the proposal that Msx-1 is a candidate gene whose expression in the cells at the amputation plane is important for the induction of a successful regenerative response

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