Neural crest cells are multi-potent, migratory, tissue-invasive cells that originate in the ectoderm of vertebrate embryos and play a central role in the development of the vertebrate body plan. A number of devastating cancers, including melanoma and neuroblastoma, are cancers of the neural crest. Moreover, neural crest cells share a number of general characteristics with metastatic tumor cells, and these two cell types have key molecular mediators in common, including Snail-family repressors and c-myc. This proposal seeks to exploit the considerable advantages of the Xenopus system in order to better understand the roles played by Snail-related factors and c-myc during normal neural crest development and in tumorigenesis, including the acquisition of invasiveness.
The aims of the grant include: 1) determining the molecular mechanisms that underlie the distinct activities of Snail-family proteins during neural crest precursor formation, neural crest emigration, and during epithelial-to-mesenchymal transitions (EMTs) in tumor cells;2) determining if c-myc regulates the expression of neural crest target genes by recruiting HAT activity to target promoters, and determining if Id3 functions as a Myc-effector during neural crest formation;3) using cDNA macroarray-based gene discovery methods to identify the key transcriptional targets of c-myc and Snail-family repressors during neural crest precursor cell formation, and during the onset of neural crest migration and 4) testing the hypothesis that such targets will also play roles in tumor progression by examining the expression of these factors, and the effects of over-expressing these factors, in a panel of epithelial tumor cell lines

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114058-05
Application #
7661623
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Snyderwine, Elizabeth G
Project Start
2005-09-26
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$243,714
Indirect Cost
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Moosmann, Julian; Ershov, Alexey; Altapova, Venera et al. (2013) X-ray phase-contrast in vivo microtomography probes new aspects of Xenopus gastrulation. Nature 497:374-7
Lander, Rachel; Nasr, Talia; Ochoa, Stacy D et al. (2013) Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation. Nat Commun 4:1542
Harney, Allison S; Meade, Thomas J; LaBonne, Carole (2012) Targeted inactivation of Snail family EMT regulatory factors by a Co(III)-Ebox conjugate. PLoS One 7:e32318
Prasad, Maneeshi S; Sauka-Spengler, Tatjana; LaBonne, Carole (2012) Induction of the neural crest state: control of stem cell attributes by gene regulatory, post-transcriptional and epigenetic interactions. Dev Biol 366:10-21
Ochoa, Stacy D; Salvador, Sally; LaBonne, Carole (2012) The LIM adaptor protein LMO4 is an essential regulator of neural crest development. Dev Biol 361:313-25
Lander, Rachel; Nordin, Kara; LaBonne, Carole (2011) The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1. J Cell Biol 194:17-25
Haldin, Caroline E; LaBonne, Carole (2010) SoxE factors as multifunctional neural crest regulatory factors. Int J Biochem Cell Biol 42:441-4
Vernon, Ann E; LaBonne, Carole (2006) Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development 133:3359-70