The proper regulation of Hox gene expression during development is crucial for normal patterning to occur along the anterior-posterior axis of the embryo. Misexpression of Hox genes often results in homeotic transformations whereby structures located in anterior regions of the embryo resemble posterior-derived structures. In vertebrate embryos, treatment with retinoic acid (RA) during specific gestation times can anteriorize the borders of Hox gene expression resulting in homeotic transformations. RA exerts transcriptional control through nuclear receptors of the RXR and RAR families by binding DNA as a heterodimer at an RA response element (RARE). Previously, our laboratory characterized an RARE in the neural enhancer of the murine Hoxd4 gene that is strictly required for its activity (Zhang et al., 2000). Cloning and sequencing of the zebrafish Hoxd4 gene reveals that the sequence and spacing of this RARE is highly conserved as well as the sequences that flank it. Other RAREs have been identified in Hox genes that are required for their expression in the developing hindbrain. The sequence and, in some cases, the spacing of these Hox RAREs are different. These differences may affect the affinity of the RXR•RAR heterodimer that bind to them which in turn may determine where their anterior borders of expression are set in the hindbrain. In order to test this hypothesis we alter the spacing and sequence of the RARE in the Hoxd4 neural enhancer. Changes that increase the heterodimer affinity for the RARE do not anteriorize transgene expression, whereas changes that decrease heterodimer affinity posteriorized transgene expression. Thus, the setting of the Hox anterior borders of expression is not a simple function of heterodimer affinity for their cognate elements. Since the sequences that flank the Hoxd4 RARE are highly conserved, they may also play a role in neural expression of Hoxd4 by recruiting factors that cooperatively interact with the RXR•RAR hete
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38539 |
| Date | January 2002 |
| Creators | Nolte, Christof D. |
| Contributors | Featherstone, Mark (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001975741, proquestno: NQ88540, Theses scanned by UMI/ProQuest. |
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