Hox genes encode homeodomain-containing transcription factors involved in the specification of structures along the anterior-posterior and secondary axes of the vertebrate embryo. Many pieces of evidence suggest that retinoic acid (RA) regulates Hox gene function. The present work involved the characterization of the transcription unit of a murine Hox gene, Hoxd4, its response to RA and its genetic interactions with Retinoic Acid Receptors (RARs) beta and gamma. / We have identified two Hoxd4 transcription start sites, P1 and P2. Multiple transcripts were identified by Northern blot, originating from both promoters and multiple polyadenylations signals. Expression of P1 transcripts in the neural tube showed an anterior border at the rhombomere 6/7 boundary, while P2 transcripts are detected more posteriorly. Somitic expression was strong up to somite 6 and weak in somite 5. After RA exposure in utero, only P1 showed a direct response to exogenous RA in the hindbrain, 4 or 24 hours after RA treatment on day 8.5 of gestation. In embryos collected 24 hours after RA treatment, wild-type mice showed a full rhombomere anteziorization of Hoxd4 expression. In contrast, Rarb null mice displayed only a partial anteriorization under the same conditions. The same holds true for the Hoxb4 gene. These results indicate that RARbeta is one of the mediators of the Hoxd4 and Hoxb4 RA-response. / Rarg null mutant mice display homeotic transformations of the cervical vertebrae that are similar to a Hoxd4 null mutant phenotype. In order to examine whether Hoxd4 and Rarg he in a common genetic pathway for patterning of the cervical region, we generated mice doubly mutant for these genes and analyzed their skeletons. For two malformations present in single mutants, namely an ectopic anterior arch in cervical vertebra 2 (C2) and the fusion of the basioccipital bone to C1, the penetrance and expressivity in double null mutants was significantly increased. Thus, we conclude that Hoxd4 and Rarg interact synergistically in the specification of these cervical vertebrae. In contrast to Rarg mutants, retinoic acid treatment of Hoxd4; Rarg double mutants on day 10.5 does not rescue normal development of C2. This result suggests that Hoxd4 mediates the retinoic acid-induced correction of this phenotype in Rarg mutants.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35881 |
| Date | January 1998 |
| Creators | Folberg, Adriana. |
| Contributors | Featherstone, Mark S. (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: 001652379, proquestno: NQ50162, Theses scanned by UMI/ProQuest. |
Page generated in 0.0014 seconds