Details of the intrinsic pathway

21 June 2000

David Vaux

Guy Salvesen is right - God IS in the details (or maybe it's the Devil…). As he (Guy, not the other two) mentioned, caspase 3, caspase 9 and Apaf-1 knock out mice have very similar phenotypes, mainly featuring excess neurons. Recently, however, caspase 3 knockouts and Apaf-1 knockouts have been bred onto a pure C57BL/6 background (1,2). In both cases several animals have survived to adulthood, and even produced live offspring. Clearly, in the mouse, neither Apaf-1 nor caspase 3 are essential for developmental cell deaths or those that maintain constancy of cell number. Does this mean that the "intrinsic" or "cytochrome c / Apaf-1 dependent" apoptosis pathway is of minor significance? Because many of the early experiments were of necessity carried out on mouse embryo fibroblasts or ES cells, it will be very interesting to see which other cell types (such as CSF-dependent hemopoietic cells) will still be able to undergo apoptosis in response to growth factor starvation or Fas ligation.

REFERENCES

1. Woo, M., Hakem, A., Elia, A. J., Hakem, R., Duncan, G. S., Patterson, B. J. & Mak, T. W. (1999) In vivo evidence that capase-3 is required for Fas-mediate apoptosis of hepatocytes. Journal of Immunology 163 4909-4916.[Medline]

2. Honarpour, N., Du, C. Y., Richardson, J. A., Hammer, R. E., Wang, X. D. & Herz, J. (2000) Adult Apaf-1-deficient mice exhibit male infertility. Developmental Biology 218 248-258. [Medline]