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Title: Genetic and molecular studies of the dominant hemimelia locus in the mouse
Author: Higgins, Maureen
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1992
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Dominant hemimelia (Dh) is a semi-dominant mutation which arose spontaneously in 1954. Dh/+ mice are asplenic, have a slightly smaller stomach and digestive tract than their + /+ siblings. They also exhibit preaxial abnormalities of the hind limb which include triphalangy of the hallux, polydactyly, oligodactyly and a reduction or absence of the tibia. The number of ribs, sternabrae and pre-sacralvertebrae is reduced. The abnormalities are more severe in homozygous animals and are usually fatal. The earliest morphological defect which can be detected is in the splanchnic mesoderm, a derivative of the lateral mesoderm. It has been hypothesised that Dh interferes with the normal structural arrangement of the cells of the splanchnic mesoderm and that all defects in Dh animals are traceable to this structure. In the introduction to this thesis it is proposed that the primary effect of the Dh mutation occurs during segmentation, i.e. somitogenesis. It is proposed that Dh disrupts the process of somitogenesis and results in the loss of the normal organised structure of the splanchnic mesoderm and in vertebral malformations. The peliotropic phenotype of Dh is a direct consequence of the combined effect of these two abnormalities. The observation that En-1, a homeobox containing gene, mapped close to or at the Dh locus prompted the work described in this thesis. The suggestion that homeobox containing genes are key genes in the control of development has been strengthened by several lines of evidence and provoked the question of whether the Dh mutation represented a mutant allele of En-1. The principal aim of this project was to determine whether Dh and En-1 were alleles of one another and, if not, devise means of identifying and cloning the Dh gene. Dh was found to map 0.7±0.4 cM proximal to En-1 and 1.1±0.4 distal to Emv-17 and is therefore unlikely to represent a mutant allele of en-1. The physical localisation of the Dh locus was attempted using pulsed field gel electrophoresis (PFGE). The PFGE map around En-1, which encompasses 1500kb, detected the presence of 5 CpGG islands and therefore, by inference, genes. Two of these CpG islands are within 800kb 3' to En-1, the remaining three islands are situated within 600kb 5' to En-1. Whether any of these islands are associated with the Dh locus will depend on the ratio of genetic to physical distance in this region of the genome. The localisation of the Dh locus and the orientation of the En-1 gene relative to the chromosome was attempted via the mapping of the recombination breakpoint of the four animals recovered from the linkage analysis which were recombinant between Dh and En-1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available