Papalopoulou, Athanasia; (1991) Analysis of vertebrate homeobox containing genes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The homeobox is a 180bp motif that was originally identified as a conserved motif in a number of Drosophila genes involved in embryonic pattern formation. Homeobox containing genes have subsequently been isolated from the genome of a wide range of organisms, including vertebrates where it is hoped that they will provide insight into the process of regional specification. This work has focused on the regulation and expression of the homeobox genes of one of the four clusters in the mouse, Hox 2. The patterns of expression were studied by Northern blotting in foetal and adult tissues. Most Hox 2 genes showed expression at high levels in the 12.5 day mouse embryo and expression is often maintained in the adult. Expression of the Hox 2 genes showed tissue- and stage-specific control. Sequence comparisons revealed that certain genes from different clusters, referred to as subfamilies, show extended sequence relatedness and occupy similar positions within clusters, supporting the hypothesis that they are evolutionarily related. Comparison of their expression patterns has revealed both similarities and tissue-specific differences. Hox 2 genes displayed a complex transcription pattern in the embryo with multiple transcripts for each gene. Deletion and transfection experiments have identified sequences in the 3-untranslated region that are important for the regulation of Hox 2.1 gene expression. In an attempt to identify molecules that regulate homeobox genes, the effect of Retinoic acid (RA) was studied. In vitro experiments showed that homeobox gene expression is regulated during RA-induced differentiation of cultured cells. A correlation exists between gene position within the cluster and the anterior boundaries of expression of the Hox,2 genes. A correlation was also observed between gene location the cluster and the degree of response to RA, both in tissue culture cells and in Xenopus embryos. RA was also found to profoundly affect patterning of the rostrocaudal embryonic axis in Xenopus. Many Hox 2 genes show high levels of expression in the hindbrain and have anterior cut-offs of expression that coincide with rhombomeric boundaries. It was found that RA is capable of disrupting the morphology of rhombomeres and may be altering positional values within the hindbrain. Taken together, these findings suggest that homeobox genes might be important for the patterning of the vertebrate CNS and may be controlled, at least in part, by molecules such as RA.

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