Mutation analysis in C. elegans:
Genetic dissection of Cell Death

Mutation analysis is used to study cell death (apoptosis) in C. elegans, the "petri-dish human."  A Kenyon alumnus, Brad Hersh, learned genetic dissection with Lac reporter genes in our Bacteria Research Lab.   He moved on to C. elegans at MIT, where he  published his research with Nobel winner Bob Horvitz.

Gene products causing cell death, or apoptosis, play essential roles in development and longevity.

  • Cell death genes turned on incorrectly cause autoimmune and neurodegenerative diseases.
  • Cell death genes turned off incorrectly cause cancer.
In C. elegans, some cell death proteins consume dead cells -- caspases.
Other cell death proteins are activators or inhibitors of other cell death proteins.
We can identify gain-of-function and loss-of-function mutations in  all the different genes and promoters involved in cell death, then analyze their combinations and phenotypes using logic based on the lac operon.

For example:

  • Loss-of-function in ced-3, ced-4, or egl-1 prevent cell death.
  • Gain-of-function in ced-9 prevents cell death.
  • Both CED-4 and CED-9 proteins localize to the mitochondria; CED-4 must translocate to the nucleus to cause cell death.
  • CED-4 translocation was blocked by a gain-of-function mutation in ced-9.
Based on this and other evidence, Hersh came up with this model of gene product interaction: