? ? This proposal is designed to provide the candidate a 1-2 year period of mentored research in the laboratory of Dr. A. T. Look (at the Dana Farber), a pioneer in the use of zebrafish as a model to study development of the peripheral sympathetic nervous system and neuroblastoma. This proposal is also designed to support the candidate as an independent investigator during the first 3 years of a new faculty appointment in a neurobiology/oncology department. The goal of this application is to use the zebrafish as a model to dissect the molecular components of Foxd3-mediated neural crest cell survival and migration and to determine if this pathway promotes metastasis of neural crest-derived tumors in vivo. The zebrafish, with its close synteny to the human genome and its conserved molecular pathways regulating the development of tissues and organs, offers a powerful tool with which to conduct such research. The candidate has identified and characterized a zebrafish mutant Foxd3 line that has specific neural crest cell survival and migration defects and has identified the Snail b transcription factor as a critical mediator of Foxd3 function. The underlying hypothesis of this application is that knowledge of the Foxd3 pathway will provide an understanding of how neural crest cells migrate and survive in foreign environments, a requirement for the metastasis of neural crest-derived tumors.
In Aim 1, genetic epistasis and biochemistry will determine if Foxd3 directly activates snail b expression in neural crest cells, and whether Snail b represses apoptosis and cell migration by repressing the expression of the promising candidates, puma and e-cadherin, respectively.
In Aim 2, GFP-labeled neural crest cells from Foxd3 mutant and wild-type siblings will be analyzed by microarray to identify and analyze additional downstream targets of Foxd3-mediated neural crest cell survival and migration.
In Aim 3, Foxd3 and snail b will be over-expressed in developing neural crest cells to examine their potential roles in promoting metastasis in established zebrafish neural crest tumor models. During normal development, cells from the neural tube detach, activate survival programs and migrate to distant regions of the embryo. This process is similar to the way cells behave during metastasis in human cancers. The goal of this application is to find the genes involved in the normal embryonic survival and migration programs and determine if these genes are aberrantly activated during cancer metastasis. ? ? ?
| Jimenez, Laura; Wang, Jindong; Morrison, Monique A et al. (2016) Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis. Dis Model Mech 9:389-400 |
| Jette, C A; Flanagan, A M; Ryan, J et al. (2008) BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals. Cell Death Differ 15:1063-72 |
| Smolen, Gromoslaw A; Schott, Benjamin J; Stewart, Rodney A et al. (2007) A Rap GTPase interactor, RADIL, mediates migration of neural crest precursors. Genes Dev 21:2131-6 |
