Nascone-Yoder Lab

North Carolina State University

Chemical Genetics: Screening small molecules in frog embryos


WntMolecular pathway identification

By screening commercially available small molecule inhibitor compounds and other chemical agents known to modulate specific signal transduction pathways, we have revealed roles for retinoic acid (RA) (Lipscomb et al., 2006) and Rho GTPase (Reed et al., 2009) signaling in gut morphogenesis.

Components of the Non-canonical Wnt Pathway
©Trends Genet. 2002 Sep;18(9):447-55.
credit: Dina Myers and Diane Sepich

Drug discovery

By screening novel compounds (synthesized by a collaborator, Alex Deiters), we have identified new drug-like smallmolecules that affect the cellular processes involved in gut development. Because similar processes are involved in diseases such as cancer and fibrosis, these compounds may be leads for anti-fibrotic or anti-metastatic drugs (see Dush et al., 2011).

 

 

 

Developmental Toxicology

Because of their rapid development, transparency, ease of use, and low cost, frog embryos are routinely employed in ecotoxicological assessments to identify potential human teratogens and developmental toxicants. By identifying the classes of chemical compounds that perturb digestive organ development in frogs, we are contributing to the assessment and identification of potential anthropogenic toxins--with additional implications for the role of environmental chemicals in global amphibian population decline (see also our work on Gut Evolution). Moreover, considering the unexplained high frequency of intestinal malrotation in the human population, such strategies may provide new insight into the role of the environment in the etiology of digestive organ birth defects.

 

Perturbation of gut morphogenesis by a small molecule

Control tadpoles (left panel) have long, narrow digestive tracts (yellow) that rotate in a counterclockwise spiral. In contrast, tadpoles exposed to a Rho kinase inhibitor develop short, broad digestive tracts that remain uncoiled.

Chemical genetic approaches have several advantages over standard knockout or mutagenesis strategies:

  • control over precisely when a particular protein’s activity is modulated
  • the potential to wash away the chemical and restore normal function at a later time point in development
  • the cost-effective convenience of screening for a phenotype in a single generation.

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