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Title: The role of mutants in the study of vertebrate limb development : analysis of hypodactyly in the mouse and polydactyly in the chick
Author: Robertson, Katherine Ella
ISNI:       0000 0001 3526 7870
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1997
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Vertebrate limb mutants are a valuable source of information on how the vertebrate limb normally develops. This thesis examines cellular and molecular aspects of limb development in the mouse mutant hypodactyly (Hd) and the chick mutant Talpid3 (ta3). Hypodactyly heterozygotes (Hd/+) show a reduction of hindlimb digit I, while homozygotes (Hd/Hd) have only one digit on all four limbs. I have analysed Hd/Hd and Hd/+ limb morphology in adulthood and throughout embryogenesis. Alterations in adult limb morphology are associated with reductions in size and shape of developing limb buds and in the number of digital blastemas that develop. The polarising region and apical ectodermal ridge (AER) are required for limb outgrowth and patterning. Hd mutant limbs have polarising activity and a well defined AER which persists for longer than in wildtype embryos. Sonic hedgehog (Shh) and fibroblast growth factor 4 (Fgf4), are expressed in the polarising region and apical ectodermal ridge respectively. In Hd/Hd mutants, expression of these genes is slightly prolonged. Hoxd genes are downstream targets of Shh, and are important in patterning the limb. Expression of both Hoxd13 and Hoxd11 are slightly altered in Hd/Hd limbs. In addition, loss of digits in hypodactyly is associated with an increase in mesenchymal cell death in developing limbs and an inability of limb mesenchymal cells to produce cartilage in culture. Talpid3 (ta3) homozygotes have polydactylous limbs with up to eight morphologically similar digits. I found that there is a graded distribution of polarising activity in ta3 limb bud mesenchyme, with ta3 anterior mesenchyme having very weak ectopic polarising activity. Shh is posteriorly localised in ta3 limbs and therefore not associated with weak polarising activity in anterior mesenchyme. In contrast, Bmp2 and Bmp7 are expressed uniformly across the antero-posterior axis, and Fgf4 transcripts are present throughout the entire apical ectodermal ridge.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Mesenchymal cell behaviour; Ectodermal jacket