SUMMARY Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A4 hydrolase, which catalyzes the final step in the synthesis of leukotriene B4 (LTB4), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB4 reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.

Neuronal activity and neurotrophins play a central role in the formation, maintenance, and plasticity of dendritic arbors. Here, we show that neuronal activity, mediated by electrical stimulation, KCl depolarization, or cholinergic receptor activation, promotes reversible dendrite formation in sympathetic neurons and that this effect is enhanced by NGF. Activity-dependent dendrite formation is accompanied by increased association of HMW MAP2 with microtubules and increased microtubule stability. Inhibition of either CaMKII or the MEK-ERK pathway, both of which phosphorylate MAP2, inhibits dendrite formation, but inhibition of both pathways simultaneously is required for dendrites to retract. These data indicate that neuronal activity signals via CamKII and the ERKs to regulate MAP2:microtubule interactions and hence reversible dendrite stability, and to provide a mechanism whereby activity and neurotrophins converge intracellularly to dynamically regulate dendritic morphology.

Recent evidence indicates that the p53 tumor suppressor protein, and its related family member, p73, play an essential role in regulating neuronal apoptosis in both the developing and injured, mature nervous system. In the developing nervous system, they do so by regulating naturally-occurring cell death in neural progenitor cells and in postmitotic neurons, acting to ensure the apoptosis of cells that either do not appropriately undergo the progenitor to postmitotic neuron transition, or that fail to compete for sufficient quantities of trophic support. Somewhat surprisingly, in developing postmitotic neurons, p53 plays a proapoptotic role, while a naturally-occurring, truncated form of p73, DNp73, antagonizes p53 and plays an anti-apoptotic role. In the mature nervous system, numerous studies indicate that p53 is essential for the neuronal death in response to a variety of insults, including DNA damage, ischemia and excitotoxicity. It is likely that all of these insults culminate in DNA damage, which may well be a common trigger for neuronal apoptosis. In this regard, the signaling pathways that are responsible for triggering p53-dependent neuronal apoptosis are starting to be elucidated, and involve cell cycle deregulation and activation of the JNK pathway. Finally, accumulating evidence indicates that p53 is perturbed in the CNS in a number of neurodegenerative disorders, leading to the hypothesis that longterm oxidative damage and/or excitotoxicity ultimately trigger p53-dependent apoptosis in the chronically degenerating nervous system. Cell Death and Differentiation (2000) 7, 880 ± 888.