While guided cell migration plays a critical role in normal skin development and wound healing, the cell biological mechanisms that guide wound closure or the developing skin remain poorly understood. We and others have previously shown that Missing in Metastasis (MIM) is a defining member of a novel class of membrane associated BAR (I-BAR) domain protein that regulates the actin cytoskeleton. We have used Drosophila border cell migration to provide the first genetic evidence that I-BAR proteins regulate directed cell migration through a novel epidermal growth factor-- dependent steering mechanism. Our working hypothesis is that pro-endocytic endophilin/CD2AP/cortactin enhance endocytosis and migration, while the anti-endocytic protein MIM spatially inhibits endocytosis to provide a directional signal during skin development and wound healing. The studies proposed in the BIRT revision extend the parent grant studies to migratory systems in skin and focuses on identifying additional proteins that work with MIM to direct cell migration. We will team with Professor Tobias Meyer, a prominent systems biologist at Stanford and an expert on high-throughput cell imaging analysis. The Oro-Meyer research team will be uniquely suited to carry out this innovative approach. The collaboration is built on our expertise in the genetics of development, and the Meyer lab's expertise in live cell imaging and siRNA screening. We will first identify which well characterized migratory system uses MIM-dependent steering. Next, using high throughput migration assays and cell tracking algorithms, we will perform a genome wide siRNA screen for genes like MIM that complement loss of cortactin. Our milestones are to identify vertebrate cell types that use MIM to steer toward their migratory cues and to identify 10 genes in the siRNA screen for further validation with our in vivo assays. Identification of novel components of the MIM-dependent steering mechanisms will provide key insights into understanding of how cells normally move to their desired locations during development and how tumor cells may use similar mechanisms during cancer metastasis.
Guided cell migration is used during normal skin development and wound healing to bring tissues to their proper locations. The Missing in Metastasis (MIM) protein is part of a novel steering mechanism that cells use to respond to migratory cues such as the epidermal growth factor, but what other proteins work with MIM remains unknown. We will team with Professor Tobias Meyer, a prominent systems biologist at Stanford, to perform a genome wide screen for genes that function like MIM. Identification of novel components of the MIM-dependent steering mechanisms will provide key insights into organ development, wound healing, and cancer metastasis.
| Drummond, Michael L; Li, Mischa; Tarapore, Eric et al. (2018) Actin polymerization controls cilia-mediated signaling. J Cell Biol 217:3255-3266 |
| Melo, Sandra P; Lisowski, Leszek; Bashkirova, Elizaveta et al. (2014) Somatic correction of junctional epidermolysis bullosa by a highly recombinogenic AAV variant. Mol Ther 22:725-33 |
| Atwood, Scott X; Oro, Anthony E (2014) ""Atypical"" regulation of Hedgehog-dependent cancers. Cancer Cell 25:133-4 |
| Atwood, Scott X; Whitson, Ramon J; Oro, Anthony E (2014) Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med 4:a013581 |
| Atwood, Scott X; Whitson, Ramon J; Oro, Anthony E (2013) ""Patch""ing up our tumor signaling knowledge. J Invest Dermatol 133:1131-3 |
| Woo, Wei-Meng; Atwood, Scott X; Zhen, Hanson H et al. (2013) Rapid genetic analysis of epithelial-mesenchymal signaling during hair regeneration. J Vis Exp :e4344 |
| Yucel, Gozde; Altindag, Banu; Gomez-Ospina, Natalia et al. (2013) State-dependent signaling by Cav1.2 regulates hair follicle stem cell function. Genes Dev 27:1217-22 |
| Aasi, Sumaira; Silkiss, Rona; Tang, Jean Y et al. (2013) New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol 149:242-3 |
| Atwood, Scott X; Li, Mischa; Lee, Alex et al. (2013) GLI activation by atypical protein kinase C ?/? regulates the growth of basal cell carcinomas. Nature 494:484-8 |
| Chang, Anne Lynn S; Oro, Anthony E (2012) Initial assessment of tumor regrowth after vismodegib in advanced Basal cell carcinoma. Arch Dermatol 148:1324-5 |
Showing the most recent 10 out of 20 publications
