Although many genes have been implicated in the pathogenesis of common neurodegenerative diseases, the genetic and cellular mechanisms that maintain neuronal integrity during normal aging remain elusive. Here we show that Caenorhabditis elegans touch receptor and cholinergic neurons display age-dependent morphological defects, including cytoskeletal disorganization, axon beading, and defasciculation. Progression of neuronal aging is regulated by DAF-2 and DAF-16 signaling, which also modulate adult life span. Mutations that disrupt touch-evoked sensory activity or reduce membrane excitability trigger accelerated neuronal aging, indicating that electrical activity is critical for adult neuronal integrity. Disrupting touch neuron attachment to the epithelial cells induces distinct neurodegenerative phenotypes. These results provide a detailed description of the age-dependent morphological defects that occur in identified neurons of C. elegans, demonstrate that the age of onset of these defects is regulated by specific genes, and offer experimental evidence for the importance of normal levels of neural activity in delaying neuronal aging. In the nematode Caenorhabditis elegans, age-dependent morphological changes are widespread in somatic tissues (2-4). However, there is little evidence for neuronal aging in C. elegans (3). The observations by Herndon et al. (3) suggest that neuronal loss or axon guidance defects do not occur in the aging C. elegans nervous system. It was also shown that whereas nuclear membranes of other somatic cell nuclei undergo drastic age-dependent deterioration, those of neuronal nuclei remain relatively intact in aging animals (4).There is, however, a clear age-dependent behavioral decline in C. elegans, including decrease in pharyngeal pumping, locomotion and chemotaxis (5). Evidence suggests that failure in neuronal activity could play a direct role in age-dependent behavioral deterioration. Cai and Sesti (6) showed that age-dependent oxidation of the C. elegans potassium channel KVS-1 causes sensory loss and that protection of neuronal KVS-1 from oxidation rescues agedependent decline in chemotaxis behavior. Electrical activity has been shown to be important for neuronal development (7) and was recently implicated in the survival or maintenance of adult mammalian and Drosophila neurons (8, 9). However, it is unclear how electrical activity promotes the integrity of adult neurons.In this paper, we address whether more subtle, subcellular changes occur in the aging C. elegans nervous system. Our results indicate that C. elegans neurons do develop age-dependent changes. Moreover, we show that electrical activity and normal attachment to the neighboring epithelial cells are required for the maintenance of adult touch receptor neurons.

While endocytosis can regulate morphogen distribution, its precise role in shaping these gradients is unclear. Even more enigmatic is the role of retromer, a complex that shuttles proteins between endosomes and the Golgi apparatus, in Wnt gradient formation. Here we report that DPY-23, the C. elegans mu subunit of the clathrin adaptor AP-2 that mediates the endocytosis of membrane proteins, regulates Wnt function. dpy-23 mutants display Wnt phenotypes, including defects in neuronal migration, neuronal polarity, and asymmetric cell division. DPY-23 acts in Wnt-expressing cells to promote these processes. MIG-14, the C. elegans homolog of the Wnt-secretion factor Wntless, also acts in these cells to control Wnt function. In dpy-23 mutants, MIG-14 accumulates at or near the plasma membrane. By contrast, MIG-14 accumulates in intracellular compartments in retromer mutants. Based on our observations, we propose that intracellular trafficking of MIG-14 by AP-2 and retromer plays an important role in Wnt secretion.

A set of conserved molecules guides axons along the metazoan dorsal-ventral axis. Recently, Wnt glycoproteins have been shown to guide axons along the anterior-posterior (A/P) axis of the mammalian spinal cord. Here, we show that, in the nematode Caenorhabditis elegans, multiple Wnts and Frizzled receptors regulate the anterior migrations of neurons and growth cones. Three Wnts are expressed in the tail, and at least one of these, EGL-20, functions as a repellent. We show that the MIG-1 Frizzled receptor acts in the neurons and growth cones to promote their migrations and provide genetic evidence that the Frizzleds MIG-1 and MOM-5 mediate the repulsive effects of EGL-20. While these receptors mediate the effects of EGL-20, we find that the Frizzled receptor LIN-17 can antagonize MIG-1 signaling. Our results indicate that Wnts play a key role in A/P guidance in C. elegans and employ distinct mechanisms to regulate different migrations.