The SLC36 transporter Pathetic is required for extreme dendrite growth in Drosophila sensory neurons

How cells achieve their correct size and how this relates to organ size control are fundamental, unresolved questions in biology. As animals grow, most tissues scale proportional to animal growth by the addition of new cells. In contrast, nervous system growth largely entails the growth of existing cells. For example, many types of sensory neurons are born early and must grow continuously during animal development to maintain coverage of a growing receptive field (Bloomfield and Hitchcock 1991; Parrish et al. 2009). Within the nervous system, different types of neurons have different growth requirements, depending on the size and complexity of their dendrite and axon arbors. For example, mature cerebellar Purkinje neurons have dendrites that are more than two orders of magnitude longer than dendrites of nearby granule cells (Fiala et al. 2008). Likewise, dendrite arbor size scales with increased body size for many types of neurons across phylogeny (Purves and Lichtman 1985); thus, neurons in larger animals must support greater growth demands. Given this enormous range in cell size, it seems likely that distinct mechanisms must exist to support growth in small and large neurons; however, whether neurons with extreme growth requirements, such as Purkinje neurons, have specialized machinery to support their growth demands remains unknown. Size control in neurons depends in part on specification of neuronal type. Some neurons have an intrinsic growth program that operates largely independently of external influences. For example, the size and shape of some isolated retinal ganglion cells grown in culture are comparable with corresponding cells in vivo, suggesting that growth properties in these neurons are intrinsically encoded (Montague and Friedlander 1991). Likewise, following widespread genetic ablation of ganglion cells, spared ganglion cells adopt a normal size independently of contacts with other ganglion cells, further suggesting that size is intrinsically determined in ganglion cells (Lin et al. 2004). In some scenarios, the expression of particular transcription factors dictates dendrite arbor size and complexity. For example, levels of the transcription factor cut dictate dendrite arbor size in Drosophila dendrite arborization (da) neurons; loss of cut reduces arbor size in da neurons with large dendrite arbors, whereas ectopic cut expression drives overgrowth of da neurons with small dendrite arbors (Grueber et al. 2003a). Similarly, levels of the MEC-3 transcription factor specify elaborate (low) or simple (high) dendrite arbors in Caenorhabditis elegans sensory neurons (Smith et al. 2013). However, the downstream factors that facilitate growth and whether they are materially different in neurons with small and large dendrite arbors remain unknown. Drosophila peripheral nervous system (PNS) neurons have type-specific dendrite arbors that vary in size by several orders of magnitude in total dendrite length (Grueber et al. 2002), providing a tractable system to study dendrite growth control. Here we report our identification and characterization of path, which encodes a putative amino acid transporter that is broadly expressed in neurons and nonneuronal cells but is preferentially required for growth in neurons with large dendrite arbors. Dendrite growth in different types of neurons with large dendrite arbors arrests at the same value of total dendrite length in path mutants despite the fact that dendrites in these neurons normally grow to very different sizes, suggesting that path defines a program required for extreme growth in neurons. Consistent with this notion, mutation of path impinges on nutrient responses and protein homeostasis in neurons with large arbors but not in other cells. Altogether, our studies suggest that Path functions as part of a nutrient sensor in neurons and define a novel form of growth control required for extreme growth demands in neurons.