Notch signaling is required for activity-dependent synaptic plasticity at the Drosophila neuromuscular junction.

The cell-surface-signaling protein Notch, is required for numerous developmental processes and typically specifies which of two adjacent cells will adopt a non-neuronal developmental fate. It has recently been implicated in long-term memory formation in mammals and Drosophila. Here, we investigated whether activity-dependent synaptic plasticity at the neuromuscular junctions (NMJs) of third instar Drosophila larvae depends on Notch signaling. The length and number of axonal branches and number of presynaptic sites (boutons) in NMJ vary with the level of synaptic activity, so we increased activity at the NMJ by two complementary methods: increasing the chronic growth temperature of third instar larvae from 18 to 28 degrees C and using the double-mutant ether-a-gogo,Shaker (eagSh), both of which increase NMJ size and bouton count. Animals homozygous for the functionally null, temperature-sensitive Notch alleles, N(ts1) and N(ts2), displayed no activity-dependent increase in NMJ complexity when reared at the restrictive temperature. Dominant-negative Notch transgenic expression also blocked activity-dependent plasticity. Ectopic expression of wild-type Notch and constitutively active truncated Notch transgenes also reduced activity-dependent plasticity, suggesting that there is a "happy medium" level of Notch activity in mediating NMJ outgrowth. Last, we show that endogenous Notch is primarily expressed in the presynaptic cell bodies where its expression level is positively correlated with motor neuron activity.

Metabolic implications for the mechanism of mitochondrial endosymbiosis and human hereditary disorders.

The endosymbiosis of proto-mitochondrial prokaryotes (PMP) into proto-eukaryotic host-cells was a major advance in eukaryotic evolution. The nature of the initial relationship remains the subject of controversy. Various conceptual models have been proposed, but none has definitive support. We construct a model of inter-species interactions based upon well-established respiratory pathways, describing the respective energy gain of host-cell and PMP resulting from varying levels of cooperation. The model demonstrates conflicting evolutionary strategies ("Prisoner's Dilemmas") in the interspecies molecular transfers. Nevertheless, we show that coercion and iterated, multilevel selection on both species encourage endosymbiosis. Mutualism is favored if host-cells are significantly more effective than PMPs at gathering food. Otherwise, an unambiguous asymmetry between host-cell and PMP benefits implies that the initial relationship consisted of the host-cell deriving a reproductive advantage at the PMPs' expense-a cellular version of farming. Other initial relationships such as oxygen-detoxification mutualism and parasitism are not strongly supported by the model. We compare the model behavior with experiments on mutant human mitochondria and find the model predicts proliferation rates consistent with that data. We derive from the evolutionary dynamics counter-intuitive therapeutic targets for two human hereditary mitochondrial disorders that reflect the ongoing effect of short-term selection at the mitochondrial level.