PROGRAMMED CELL-DEATH IN THE ABSENCE OF C-FOS AND C-JUN

Programmed cell death, or apoptosis, is a normal process in the develo pment of a variety of embryonic and adult tissues, and is also observe d in several pathological conditions, Several recent studies, using bo th expression and functional assays, have implicated the transcription factor, AP-1, in the regulation of programmed cell death, and specifi cally implicate the genes c-fos and c-jun, as well as some other famil y members, If the products of the c-fos and/or c-jun genes are essenti al components in the cascade of events that leads to programmed cell d eath in mammalian cells, it follows that cell death would not occur in mice lacking functional copies of these genes. We have made use of nu ll mutations in the c-fos and c-jun genes that were produced by gene t argeting (Johnson, R. S., Spiegelman, B. M. and Papaioannou, V. E. (19 92), Cell 71, 577-586; Johnson, R. S., Van Lingen, B., Papaioannou, V. E. and Spiegelman, B. M. (1993), Genes Dev. 7, 1309-1317) to investig ate this possibility, Cell death was assayed using an in situ apoptosi s assay in c-fos null embryos and adults, c-jun null embryos, and c-fo s/c-jun double null embryos compared with control mice, The occurrence of cell death in c-fos null mice was also assessed in two experimenta l conditions that normally lead to neuronal cell death, The first was unilateral section of the sciatic nerve in neonates, which leads to th e death of anterior horn cells of the spinal cord on the operated side , The second was a genetic cross combining the weaver mutation, which causes death of cerebellar granule cells, with the c-fos mutation. Our results show that programmed cell death occurs normally in developing embryonic tissues and adult thymus and ovary, regardless of the absen ce of a functional c-fos gene, Furthermore, absence of c-fos had no ef fect on neuronal cell death in the spinal cord following sciatic nerve section, or in heterozygous weavers' cerebellae. Finally, the results show that programmed cell death can take place in embryos lacking bot h Fos and Jun.