Caspases and Their Regulation in Apoptosis during Brain Development
Cell death is an important mechanism during the mammalian brain development, with documented roles in both morphogenetic and histiogenetic degeneration. The mammalian caspase family of cysteine-containing, aspartatespecific proteases was suggested to play a pivotal role in execution of developmental apoptosis due to its homology to the cell death gene ced-3 of the nematode C. elegans. We have used the gene targeting strategy to test the biological functions of several members of the caspase family. Our results indicate that caspase-9 and caspase-3 are essential for programmed cell death and normal mouse brain development. Moreover, caspase-9 and caspase-3 form a sequential cell death cascade, as the absence of caspase-9 abolishes the cytochrome c-mediated caspase-3 activation both in vivo and in vitro and exhibits similar phenotypes to those of caspase-3 deficiency. To test whether the activation of caspase-3 in the mammalian brain is also regulated by Bax and BclxL, homologues of the pro-apoptotic gene eg1-1 and antiapoptotic gene ced-9 in C. elegans, respectively, we conducted epistatic genetic analysis in caspase-3/bc1-x double mutants. The absence of caspase-3 rescued the ectopic cell death of post-mitotic neurons caused by the BclxL deficiency, indicating an evolutionary conserved cell death pathway. However, Bax and BclxL are expressed only in post-mitotic neurons, in contrast to caspase-3, which is activated in the proliferative population and specific brain regions associated with morphogenesis. Moreover, unlike caspase-3 or -9 deficiency, Bax-deficient mutants exhibited a normal amount of cell death in the early developing brain. These results indicate additional signaling pathways in early brain development, preventing a random, haphazard activation of caspases. The Jun N-terminal kinase (JNK) signaling pathway appears to be an important mechanism that regulates the brain region-specific activation of caspases. In the absence of Jnkl and Jnk2 genes, both encoding a somatic form of JNK, there is reduced apoptosis in the hindbrain, leading to neural tube defect and widespread cell death coupled with ectopic caspase-3 activation in the forebrain. Taken together, these results suggest complex regulation mechanisms and distinct functions of caspase activation in mammalian brain development.
KeywordsChrome Retina Serine Tral Stim
Unable to display preview. Download preview PDF.
- Ip YT, Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase ( JNK)-from inflammation to development. Curr Opin Cell Biol 10: 205–219Google Scholar
- Kaufman MH (1992) The atlas of mouse development. Academic Press, San DiegoGoogle Scholar
- Smith JL, Schoenwolf GC (1997) Neurulation: coming to closure. Trends Neurosci 20:510–517 Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281: 1312–1316Google Scholar
- Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90: 405413Google Scholar