Ann (Parrish Lab) just had a paper published in Genes and Development about pathetic mutants! Below she describes the impetus and context for the paper, as well as the results.
The link to the full paper is found here.
A central question in growth control of multicellular organisms is how growing organisms maintain proportionality. For example, as animals grow, dendrite arbors of many neurons must expand proportionally to sustain proper connectivity and maintain coverage of their receptive field. However, different types of neurons have different growth requirements, depending on the size and complexity of their dendrite (and axon) arbors. We have been working to identify the cellular machinery that supports neuron growth with a focus on understanding whether neurons with large arbors have specialized mechanisms to support their extreme growth requirements.
From a genetic screen, we identified a mutant that selectively affects dendrite growth in neurons with large dendrite arbors without affecting dendrite growth in neurons with small dendrite arbors or the animal overall. This mutant disrupts a putative amino acid transporter, Pathetic (Path), that localizes to the cell surface and endolysosomal compartments in neurons. Although Path is broadly expressed in neurons and non-neuronal cells, mutation of path impinges on nutrient responses and protein homeostasis specifically in neurons with large dendrite arbors but not in other cells. Altogether, our results demonstrate that specialized molecular mechanisms exist to support growth demands in neurons with large dendrite arbors and define Path as a founding member of this growth program.
Shown here (Figure 1) is a confocal image of Drosophila Class IV da neurons (labeled by ppk-CD4-tdTomato) in a pathetic zygotic null mutant 3rd instar larva. Dendrite growth arrests at a fixed limit in pathetic mutant sensory neurons (cyan neurons), but in very rare cases (<0.5% of neu- rons), persistent maternal Pathetic protein rescue the mutant phenotype (red neuron), demonstrating that low levels of Pathetic are sufficient to support extreme dendrite growth in these neurons. Pathetic supports dendrite growth in part by increasing translational output, but is dispensable for growth and patterning of other larval tissues.
Shown here (Figure 2) are confocal images of Drosophila Class I (magenta) and Class IV da neurons (red), labeled by 98b-Gal4, UAS-CD4-tdGFP and ppk-CD4- tdTomato, respectively, in pathetic mutant (left) or wild type (right) 2nd instar larva (cyan). Dendrites of Drosophila dendrite arborization neurons grow continuously during larval development to maintain proportional body wall coverage, but Class IV da neurons have much larger and more elaborate dendrite arbors than Class I da neurons. Mutation of pathetic selectively affects dendrite growth in neurons with large dendrite arbors, including Class IV da neurons, doing so by affecting translational output of neurons. By contrast, pathetic is dispensable for dendrite growth in neurons with small dendrite arbors or the animal overall, demonstrating that growth of large dendrite arbors entails specialized molecular mechanisms.
