c-Jun and the transcriptional control of neuronal apoptosis

There has been considerable interest in the molecular mechanisms of apoptos is in mammalian neurons because this form of neuronal cell death is importa nt for the normal development of the nervous system and because inappropria te neuronal apoptosis may contribute to the pathology of human neurodegener ative diseases. The aim of recent research has been to identify the key com ponents of the cell death machinery in neurons and understand how the cell death programme is regulated by intracellular signalling pathways activated by the binding of neurotrophins or death factors to specific cell surface receptors. The aim of this commentary was to review research that has inves tigated the role of the Jun N-terminal kinase (JNK)/c-Jun signalling pathwa y in neuronal apoptosis, focusing in particular on work carried out with de veloping sympathetic neurons. Experiments with sympathetic neurons cultured in vitro, as well as with cerebellar granule neurons and differentiated PC 12 cells, have demonstrated that JNK/c-Jun signalling can promote apoptosis following survival factor withdrawal. In addition, experiments with Jnk(-/ -) knockout mice have provided evidence that Jnk3 may be required. for apop tosis in the hippocampus in duo following injection of kainic acid, an exci totoxin, and that Jnk1 and Jnk2 are required for apoptosis in the developin g embryonic neural tube. However, in the embryonic forebrain, Jnk1 and Jnk2 have the opposite function and are necessary for the survival of developin g cortical neurons. These results suggest that JNKs and c-Jun are important regulators of the cell death programme in the mammalian nervous system, bu t chat their biological effects depend on the neuronal type and stage of de velopment. BIOCHEM PHARMACOL 60;8:1015-1021, 2000. (C) 2000 Elsevier Scienc e Inc.