Axonal degeneration is a characteristic feature of neurodegenerative disease and nerve injury. Here, we characterize axonal degeneration in Caenorhabditis elegans neurons following laser-induced axotomy. We show that this process proceeds independently of the WLDS and Nmnat pathway, and requires the axonal clearance machinery that includes the conserved transmembrane receptor CED-1/Draper, the adaptor protein CED-6, the guanine nucleotide exchange factor complex Crk/Mbc/dCed-12 (CED-2/CED-5/CED-12) and the small GTPase Rac1 (CED-10). We demonstrate that CED-1 and CED-6 function non-cell-autonomously in the surrounding hypodermis, which we show acts as the engulfing tissue for the severed axon. Moreover, we establish a function in this process for CED-7, an ATP-binding cassette (ABC) transporter, and NRF-5, a lipid-binding protein, both associated with release of lipid-vesicles during apoptotic cell clearance. Thus, our results reveal the existence of a WLDS /Nmnat-independent axonal degeneration pathway, conservation of the axonal clearance machinery, and a function for CED-7 and NRF-5 in this process.

Spinal muscular atrophy is a devastating disease that is characterized by degeneration and death of a specific subclass of motor neurons in the anterior horn of the spinal cord. Although the gene responsible, survival motor neuron 1 (SMN1), was identified 20 years ago, it has proven difficult to investigate its effects in vivo. Consequently, a number of key questions regarding the molecular and cellular functions of this molecule have remained unanswered. We developed a Caenorhabditis elegans model of smn-1 loss-of-function using a neuron-specific RNA interference strategy to knock-down smn-1 selectively in a subclass of motor neurons. The transgenic animals presented a cell-autonomous, age-dependent degeneration of motor neurons detected as locomotory defects and the disappearance of presynaptic and cytoplasmic fluorescent markers in targeted neurons. This degeneration led to neuronal death as revealed by positive reactivity to genetic and chemical cell-death markers. We show that genes of the classical apoptosis pathway are involved in the smn-1-mediated neuronal death, and that this phenotype can be rescued by the expression of human SMN1, indicating a functional conservation between the two orthologs. Finally, we determined that Plastin3/plst-1 genetically interacts with smn-1 to prevent degeneration, and that treatment with valproic acid is able to rescue the degenerative phenotype. These results provide novel insights into the cellular and molecular mechanisms that lead to the loss of motor neurons when SMN1 function is reduced.

Food is critical for survival. Many animals, including the nematode Caenorhabditis elegans, use sensorimotor systems to detect and locate preferred food sources. However, the signaling mechanisms underlying food-choice behaviors are poorly understood. Here, we characterize the molecular signaling that regulates recognition and preference between different food odors in C. elegans. We show that the major olfactory sensory neurons, AWB and AWC, play essential roles in this behavior. A canonical G␣-protein, together with guanylate cyclases and cGMP-gated channels, is needed for the recognition of food odors. The food-odor-evoked signal is transmitted via glutamatergic neurotransmission from AWC and through AMPA and kainate-like glutamate receptor subunits. In contrast, peptidergic signaling is required to generate preference between different food odors while being dispensable for the recognition of the odors. We show that this regulation is achieved by the neuropeptide NLP-9 produced in AWB, which acts with its putative receptor NPR-18, and by the neuropeptide NLP-1 produced in AWC. In addition, another set of sensory neurons inhibits food-odor preference. These mechanistic logics, together with a previously mapped neural circuit underlying food-odor preference, provide a functional network linking sensory response, transduction, and downstream receptors to process complex olfactory information and generate the appropriate behavioral decision essential for survival.