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Frank David Macabenta
B.A., University of Guam - 2009
Thesis Advisor: Sunita Gupta Kramer, Ph.D
Graduate Program in Cell and Developmental Biology
Room D406, Piscataway
Friday, December 12, 2014
The development of a functional organ requires spatiotemporal expression and localization of signaling molecules in order to mediate proper cell migration and cell-cell matching. The dorsal vessel (DV), a mesoderm-derived muscular tube that serves as the primary circulatory organ in the fruit fly Drosophila melanogaster, is composed of bilaterally symmetric rows of cardiac progenitor cells called cardioblasts (CBs) which undergo specification, migration, and morphogenesis in order to form a central lumen. Previously conducted research has shown that the transmembrane receptor Roundabout (Robo) and its corresponding ligand Slit are necessary for negative regulation of DE-cadherin at what would become the luminal space; however, the process by which contralateral pairs of CBs initiate the cell shape changes necessary for forming the dorsal and ventral junctional domains is poorly understood. Netrins, which are a highly conserved family of laminin-type secreted proteins, are known to facilitate attraction or repulsion of axon growth cones in the developing embryonic CNS depending on the corresponding receptor – signaling via the Unc5 receptor is known to mediate repulsion of axon growth cones, while signaling via the Frazzled (Fra) receptor acts in opposition to Slit-Robo mediated repulsion in order to facilitate attraction. Additionally, a role for Unc5 in mediating lumen formation had been previously reported; as such, we investigated a potential role for Netrin-Frazzled signaling in DV formation and found that Fra is necessary for mediating proper outgrowth and attachment between contralateral CB pairs. fra mRNA is expressed in the dorsal vessel prior to and during morphogenesis. Loss-of-fra-function results in defects in adhesion domains, and expressed Fra protein accumulates at sites of attachment in a Netrin-dependent fashion. Furthermore, preliminary analysis of the two Drosophila Netrins reveals that Netrin A is expressed in distinct stripes along the overlying dorsal ectoderm but is not expressed in the DV, while Netrin B is expressed in a subset of CBs and is absent in the dorsal ectoderm. A combination of loss-of-function and overexpression studies hints at a requirement for NetA in facilitating initial migration of the CB rows, while NetB is required for the final morphogenetic events involved in lumen formation. This study provides strong evidence for a novel role for Netrins and Netrin receptors in ensuring proper development of a functional biological tube.