Cell migration and extension is essential for development. The ability of a cell or cell extension to reach its target is dependent on spatial cues and receptors that translate positional information into directed plasma membrane extension. For example, the UNC-40/DCC receptor is required to direct circumferential migrations towards the source of the ligand, UNC-6/Netrin, expressed at the ventral midline. To better understand the process of cell extension, I used a specialized process called muscle arms as a model system. In C. elegans, body wall muscles (BWMs) extend membrane projections called muscle arms to the nearest nerve cord at the midline. These muscle arms harbor the postsynaptic element of the neuromuscular junction and extend in a stereotypical and regulated manner. In a screen for muscle arm development defective (Madd) mutants, I isolated madd-2, a novel component of the UNC-40 pathway.
MADD-2 is a C-1 TRIM protein and functions cell-autonomously to direct numerous muscle and axon extensions to the ventral midline of worms. In a striking analogy, mutations in a human homologue of MADD-2, MID1, cause numerous ventral midline defects that culminate as Opitz Syndrome. How MID1 regulates midline development is unclear. MADD-2 enhances UNC-40 pathway activity by facilitating the physical interaction between UNC-40 and the downstream Rho-GEF, UNC-73. It is possible that MID1 may mediate the function of a DCC-like pathway at the ventral midline of humans. This work provides the first indication that C1-TRIM proteins may have a conserved biological role of regulating midline-oriented development events and may provide key insights into the role of MID1 in the pathogenesis of Opitz syndrome.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/27570 |
| Date | 09 June 2011 |
| Creators | Alexander, Mariam |
| Contributors | Roy, Peter John |
| 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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