BH3-only proteins: key regulators of neuronal apoptosis

The molecular mechanisms of neuronal apoptosis have been intensively studied because a considerable amount of apoptosis occurs during the normal development of the mammalian nervous system. This death is important for establishing neuronal populations of the correct size and for ensuring that neurons that contact inappropriate targets are eliminated.^{1, 2} A second reason for the interest in this area is that there is increasing evidence that apoptosis is one of the mechanisms of neuronal death following acute injuries to the nervous system, such as stroke or traumatic brain injury, and neurons often die by apoptosis in cell culture and animal models of chronic human neurodegenerative disorders.² The aim of this article is to review recent work on the function and regulation of the BH3-only subfamily of Bcl-2 proteins in neurons, with an emphasis on studies with sympathetic neurons, cerebellar granule neurons (CGNs) and motoneurons, the best studied in vitro models of neuronal apoptosis, and work that has involved the analysis of neurons from mutant mice.

An important step forward in the neuronal cell death field was the discovery in the late 1980s that the death of developing nerve growth factor (NGF)-dependent sympathetic neurons following NGF withdrawal requires de novo transcription and protein synthesis.³ This was one of the early observations that contributed to the idea of apoptosis as an active form of cell death and it proved to be true for other types of neuron deprived of survival signals, including CGNs and motoneurons. It stimulated a number of laboratories to search for genes that are transcriptionally induced in neurons undergoing apoptosis. One of the first regulated genes to be identified was the basic/leucine zipper transcription factor c-Jun, a member of the AP-1 family. The level of the c-jun mRNA and c-Jun protein increases rapidly in sympathetic neurons after NGF withdrawal, and microinjection of neutralizing antibodies against c-Jun or expression of a c-Jun dominant-negative mutant protects sympathetic neurons against NGF withdrawal-induced death,^{4, 5} as does conditional knockout of the c-jun gene in sympathetic neurons isolated from mice with a floxed c-jun gene.⁶ These observations supported the idea that NGF withdrawal-induced death involves the transcriptional induction of genes that activate the cell death programme. In addition, the observation that c-Jun N-terminal phosphorylation increases after NGF withdrawal led to the demonstration that c-Jun N-terminal kinases (JNKs) are activated in sympathetic neurons deprived of NGF and that JNK activity is required for NGF withdrawal-induced death.^{5, 7, 8, 9, 10, 11} The level of c-Jun and of c-Jun N-terminal phosphorylation also increases in CGNs following serum and KCl withdrawal, and expression of dominant-negative c-Jun inhibits cell death induced by KCl/serum deprivation.¹²

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