The mechanism by which Notch activation contributes to TDP43 toxicity is unknown. We speculate that upregulation of occurring due to direct TDP-43 RNA-binding activity or in response to TDP-43-mediated neuronal injury�Cinhibits axonal regrowth at compromised neuromuscular junctions in TDP-43 transgenic flies. Although further work is needed to address whether Notch activation contributes to axonal defects in TDP-43 transgenic flies, this model is compatible with recent findings showing that Notch inhibits regrowth of laser-transected axons in C. elegans. Hazelett et al. recently reported gene expression changes in Drosophila with overexpression and knockout of TBPH. A few notable genes were identified in our analysis as well as theirs; they found that arrow expression was changed with TBPH overexpression, and that the expression of multiple tetraspanins and acetylcholine receptors was changed with TBPH knockdown. However, the majority of genes we identified were not found in their analysis; interestingly, even within their study there was not significant overlap between genes whose expression changed with TBPH overexpression as compared to its knockout. Such discrepancy may be a result of different Gal4 driver lines used in both studies, which may reflect tissue specific regulation of TDP-43 targets. Our finding that cell cycle and Notch targets are deregulated in TDP-43 flies is at least partially supported by findings from mammalian cells. A number of studies have identified TDP-43 target genes that regulate the cell cycle or neuronal differentiation, notably including mouse Notch1, human Notch3, and the Hey mouse ortholog Hes5. However, these studies as well as ours indicate that a large percentage of the genome is regulated by TDP-43. It is therefore unlikely that there is a single gene or small group of genes that mediate TDP-43 toxicity in Drosophila; rather, activation of multiple pathways and processes are Orbifloxacin necessary for motor neuron Tulathromycin B dysregulation and degeneration. Thus, targeting of pathways rather than individual genes may be a better approach for identifying future ALS therapies. These neurons have diffuse projections to many brain regions with particularly dense innervation in limbic regions, as well as the frontal cortex, and other monoaminergic nuclei. The norepinephrine transporter is responsible for norepinephrine reuptake by the presynaptic terminal. Thus, it removes NE from the synaptic cleft and terminates noradrenergic neurotransmission, while re-charging presynaptic cells for future transmission. NET is a direct target of both antidepressants and psychostimulants. Additionally, NET mediates dopamine uptake in the prefrontal cortex. Recent work in animal models has suggested that the mechanism of drugs that treat ADHD may include inhibition of fronto-cortical NET. NE and NET, along with two other monoamines and their transporters form a complex interacting system that influences a broad range of affective states. Mouse knockouts for NET, DAT, and SERT have been used to study the pharmacological, behavioral, and anatomical consequences of disruption of these monoamine transporters. Single and multiple knockouts have been especially useful in investigations parsing the molecular actions and behavioral consequences of drugs of abuse.