Summary Background Dendrites often display remarkably complex and diverse morphologies that are influenced by developmental and environmental cues. Neuroplasticity in response to adverse environmental conditions entails both hypertrophy and resorption of dendrites. How dendrites rapidly alter morphology in response to unfavorable environmental conditions is unclear. The nematode Caenorhabditis elegans enters into a stress-resistant dauer larval stage in response to an adverse environment. Results Here we show that the IL2 bipolar sensory neurons undergo dendrite arborization and axon remodeling during dauer development. When dauer larvae are returned to favorable environmental conditions, animals resume reproductive development and IL2 dendritic branches retract, leaving behind remnant branches in post-dauer L4 and adult animals. The C. elegans furin homolog KPC-1 is required for dauer IL2 dendritic arborization and dauer specific nictation behavior. kpc-1 is also necessary for dendritic arborization of PVD and FLP sensory neurons. In mammals, furin is essential, ubiquitously expressed, and associated with numerous pathologies including neurodegenerative diseases. While broadly expressed in C. elegans neurons and epithelia, kpc-1 acts cell autonomously in IL2 neurons to regulate dauer-specific dendritic arborization and nictation. Conclusions Neuroplasticity of the C. elegans IL2 sensory neurons provides a paradigm to study stress-induced and reversible dendritic branching, and the role of environmental and developmental cues in this process. The newly discovered role of KPC-1 in dendrite morphogenesis provides insight into the function of proprotein convertases in nervous system development.

Summary Cilia and extracellular vesicles (EVs) are signaling organelles[1]. Cilia act as cellular sensory antennae, with defects resulting in human ciliopathies. Cilia both release and bind to EVs[1]. EVs are submicron-sized particles released by cells and function in both short and long range intercellular communication. In C. elegans and mammals, the Autosomal Dominant Polycystic Kidney Disease (ADPKD) gene products polycystin-1 and polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation[2]. A fundamental understanding of EV biology and the relationship between the polycystins, cilia, and EVs is lacking. To define properties of a ciliated EV-releasing cell, we performed RNAseq on 27 GFP-labeled EV releasing neurons (EVNs) isolated from adult C. elegans. We identified 335 significantly overrepresented genes, of which 61 were validated by GFP reporters. The EVN transcriptional profile uncovered new pathways controlling EV biogenesis and polycystin signaling and also identified EV cargo, which included an antimicrobial peptide and ASIC channel. Tumor necrosis associated factor (TRAF) homologues trf-1 and trf-2 and the p38 mitogen-activated protein kinase (MAPK) pmk-1 acted in polycystin signaling pathways controlling male mating behaviors. pmk-1 was also required for EV biogenesis, independent of the innate immunity MAPK signaling cascade. This first high-resolution transcriptome profile of a subtype of ciliated sensory neurons isolated from adult animals reveals the functional components of an EVN.

Organisms are often capable of modifying their development to better suit their environment. Under adverse conditions, the nematode Caenorhabditis elegans develops into a stress resistant alternative larval stage called dauer. The dauer stage is likely the primary survival stage for C. elegans in nature. Large-scale tissue remodeling during dauer conveys resistance to harsh environments in addition to behavioral changes. The environmental and genetic regulation of the decision to enter dauer has been extensively studied. However, less is known about the mechanisms regulating tissue remodeling. Changes to the cuticle and suppression of feeding in dauers lead to an increased resistance to external stressors. Meanwhile reproductive development arrests during dauer while preserving the ability to reproduce once favorable environmental conditions return. Dramatic remodeling of neurons, glia, and muscles during dauer likely facilitate dauer-specific behaviors. Dauer-specific pulsation of the excretory duct likely mediates a response to osmotic stress. The power of C. elegans genetics has uncovered some of the molecular pathways regulating dauer tissue remodeling. In addition to genes that regulate single remodeling events, several mutants result in pleiotropic defects in dauer remodeling. This review details the individual aspects of morphological changes that occur during dauer formation and discusses molecular mechanisms regulating these processes. The dauer stage provides us with an excellent model for understanding phenotypic plasticity and remodeling from the individual cell to an entire animal.

Stress-induced changes to the dendritic architecture of neurons have been demonstrated in numerous mammalian and invertebrate systems. Remodeling of dendrites varies tremendously among neuron types. During the stress-induced dauer stage of Caenorhabditis elegans, the IL2 neurons arborize to cover the anterior body wall. In contrast, the FLP neurons arborize to cover an identical receptive field during reproductive development. Using timecourse imaging, we show that branching between these two neuron types is highly coordinated. Furthermore, we find that the IL2 and FLP arbors have a similar dendritic architecture and use an identical downstream effector complex to control branching; however, regulation of this complex differs between stress-induced IL2 branching and FLP branching during reproductive development. We demonstrate that the unfolded protein response (UPR) sensor IRE-1, required for localization of the complex in FLP branching, is dispensable for IL2 branching at standard cultivation temperatures. Exposure of ire-1 mutants to elevated temperatures results in defective IL2 branching, thereby demonstrating a previously unknown genotype by environment interaction within the UPR. We find that the FOXO homolog, DAF-16, is required cell-autonomously to control arborization during stress-induced arborization. Likewise, several aspects of the dauer formation pathway are necessary for the neuron to remodel, including the phosphatase PTEN/DAF-18 and Cytochrome P450/DAF-9. Finally, we find that the TOR associated protein, RAPTOR/DAF-15 regulates mutually exclusive branching of the IL2 and FLP dendrites. DAF-15 promotes IL2 branching during dauer and inhibits precocious FLP growth. Together, our results shed light on molecular processes that regulate stress-mediated remodeling of dendrites across neuron classes.

In human neurodegenerative diseases, toxic protein aggregates can spread between neurons to promote pathology. In the transparent genetic animal model C. elegans, stressed neurons can concentrate fluorescently tagged protein aggregates and organelles and extrude them in large, nearly soma-sized, membrane-bound vesicles called exophers that enter neighboring cells. C. elegans exophergenesis may occur by mechanisms analogous to those that enable aggregate spreading in the human brain in neurodegenerative disease. Here we report on aggresome-like biology in stressed C. elegans neurons that influences exophergenesis. We show that C. elegans intermediate filament proteins IFD-1 and IFD-2 can assemble into juxtanuclear structures with characteristics similar to mammalian aggresomes and document that these intermediate filaments are required cell autonomously for efficient exopher production. IFD-concentrating structures expand with age or neuronal stress level, can associate with neurotoxic polyglutamine expansion protein HttQ74, and depend upon orthologs of mammalian adapter proteins, dynein motors, and microtubule integrity for collection of aggregates into juxtanuclear compartments. IFD homolog human neurofilament light chain hNFL can substitute for C. elegans IFD-2 proteins in promoting exopher production, indicating conservation of the capacity of intermediate filaments to influence neuronal extrusion. In sum, we identify an unexpected requirement for specific intermediate filaments, counterparts of human biomarkers of neuronal injury and disease, and major components of Parkinson’s disease Lewy bodies, in large vesicle extrusion from stressed neurons.