![]() Regulators of the intrinsic apoptosis pathway including Bcl-2–associated X (BAX) protein and Bcl-2 have been implicated in this process ( Garcia et al., 1992), and mice lacking a functional BAX gene lose significantly fewer neurons during development ( Deckwerth et al., 1996 White et al., 1998). In these neurons, loss of NGF signaling results in rapid degeneration ( Gorin and Johnson, 1979). Developmental apoptosis has been extensively studied in sympathetic and dorsal root ganglion (DRG) neurons that depend on NGF for their survival ( Levi-Montalcini and Booker, 1960 Crowley et al., 1994). The establishment of peripheral innervation during development requires axonal outgrowth to target regions and subsequent refinement of connectivity through the removal of exuberant neuronal processes and the elimination of excess neurons via apoptosis ( Oppenheim, 1991 Luo and O’Leary, 2005). DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. ![]()
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