Forward genetic screens in the mouse are contributing significantly to our understanding of basic mammalian development and human disease. In one such screen, our laboratory has identified the novel mouse gumby mutant, which affects the development of the neural and vascular systems.
Here, I describe the characterization of the gumby mutant phenotype and the identification of its causative mutation in a novel, vertebrate-specific gene, which is one of the genes deleted in patients affected by Cri du Chat Syndrome that exhibit mental retardation and craniofacial deficits.
Expression and phenotypic analyses revealed a requirement for the gumby gene in the facial nerve axon guidance and angiogenesis. Lately, it has become evident that many common mechanisms and molecules operate during neural and vascular development. My results suggest that the gumby gene is an attractive candidate for regulating both processes and its analysis in the future may help us understand how the navigational mechanisms for both systems are intertwined.
My studies show that gumby is a cytoplasmic protein that is present in many embryonic and adult tissues. In yeast-two-hybrid assays gumby interacts with a member of the highly conserved Wnt pathway - Dishevelled 2 (Dvl2). In both Dvl2-/- and gumby homozygotes, the level of the cardiac neural crest cell marker Plexin2A is decreased. The three branches of the Wnt pathway have been shown to regulate a wide range of events during embryogenesis and adult homeostasis, and subsequently have been implicated in multiple human pathologies. Taken together my data suggest that gumby may be required for Wnt signaling in angiogenesis and/or facial nerve guidance. Given that Wnt signaling has been shown to play key roles in axon guidance, gumby and its roles in Wnt signaling may also contribute to the mental retardation seen in patients with Cri du Chat Syndrome. Thus, further analyses of molecular and biologic roles of gumby will provide important avenues for understanding the cell biology of human disease.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/32949 |
| Date | 05 September 2012 |
| Creators | Rivkin, Elena |
| Contributors | Cordes, Sabine |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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