Congenital heart defects afflict nearly 1% of all newborns, and are found in as many as 10% of stillborn babies. Among the genetic causes of heart disease are mutations in the Nkx2-5 transcription factor. What is currently known about Nkx2-5 is an example of how much can be learned by examining development in organism that make analogous structures to those in human. Nkx2-5 is a homologue of the fruit fly gene, tinman. Tinman received its name because flies without this gene fail to form a heat, like the tinman in the Wizard of OZ. Humans with only a single normal copy of Nkx2-5 have congenital heart defects ranging form atrial septal defects, and conduction problems to conotruncal defects and tetrology of Fallot. So far, Nkx2-5 seems to be the single relevant tinman related gene for cardiac development in mammals, but in the frog Xenopus laevis, there are three related genes, Xnkx2-3, 2-5 and 2-10 all present as the heart forms. We propose studies aimed at testing each of these genes for unique and overlapping function in heart development. We will be using antisense oligonucleotide based approaches to reduce specific gene expression, and mRNA addition experiments to establish which gene product can rescue depletion of the others. We will also examine the use of a new transposon, Sleeping Beauty, for generation of transgenic embryos for this study. We propose that in Xenopus the multiple functions of the Nkx2-5 gene in humans have been split up, and thus provide a unique opportunity to better understand the function of this medically important gene.
| Hayes, Michael H; Weeks, Daniel L (2016) Amyloids assemble as part of recognizable structures during oogenesis in Xenopus. Biol Open 5:801-6 |
| Gazdag, Emese; Jacobi, Ulrike G; van Kruijsbergen, Ila et al. (2016) Activation of a T-box-Otx2-Gsc gene network independent of TBP and TBP-related factors. Development 143:1340-50 |
| Li, You E; Allen, Bryan G; Weeks, Daniel L (2012) Using ?C31 integrase to mediate insertion of DNA in Xenopus embryos. Methods Mol Biol 917:219-30 |
| Bartlett, Heather; Veenstra, Gert Jan C; Weeks, Daniel L (2010) Examining the cardiac NK-2 genes in early heart development. Pediatr Cardiol 31:335-41 |
| Bartlett, Heather L; Escalera 2nd, Robert B; Patel, Sonali S et al. (2010) Echocardiographic assessment of cardiac morphology and function in Xenopus. Comp Med 60:107-13 |
| Allen, Bryan G; Weeks, Daniel L (2009) Bacteriophage phiC31 integrase mediated transgenesis in Xenopus laevis for protein expression at endogenous levels. Methods Mol Biol 518:113-22 |
| Chesneau, Albert; Sachs, Laurent M; Chai, Norin et al. (2008) Transgenesis procedures in Xenopus. Biol Cell 100:503-21 |
| Bartlett, Heather L; Weeks, Daniel L (2008) Lessons from the lily pad: Using Xenopus to understand heart disease. Drug Discov Today Dis Models 5:141-146 |
| Bartlett, Heather L; Sutherland, Lillian; Kolker, Sandra J et al. (2007) Transient early embryonic expression of Nkx2-5 mutations linked to congenital heart defects in human causes heart defects in Xenopus laevis. Dev Dyn 236:2475-84 |
| Jacobi, Ulrike G; Akkers, Robert C; Pierson, Elisabeth S et al. (2007) TBP paralogs accommodate metazoan- and vertebrate-specific developmental gene regulation. EMBO J 26:3900-9 |
Showing the most recent 10 out of 17 publications
