An intestinal sphingolipid confers intergenerational neuroprotection.

In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here we show that feeding Caenorhabditis elegans with ursolic acid, a natural plant product, improves axon transport and reduces adult-onset axon fragility intergenerationally. Ursolic acid provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate, a bioactive sphingolipid. Intestine-to-oocyte sphingosine-1-phosphate transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. Sphingosine-1-phosphate acts intergenerationally by upregulating the transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatial regulation of sphingolipid metabolism is critical, as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.

Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism.

Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose.

Atypical TGF-ß signaling controls neuronal guidance in Caenorhabditis elegans.

Coordinated expression of cell adhesion and signaling molecules is crucial for brain development. Here, we report that the Caenorhabditis elegans transforming growth factor ß (TGF-ß) type I receptor SMA-6 (small-6) acts independently of its cognate TGF-ß type II receptor DAF-4 (dauer formation-defective-4) to control neuronal guidance. SMA-6 directs neuronal development from the hypodermis through interactions with three, orphan, TGF-ß ligands. Intracellular signaling downstream of SMA-6 limits expression of NLR-1, an essential Neurexin-like cell adhesion receptor, to enable neuronal guidance. Together, our data identify an atypical TGF-ß-mediated regulatory mechanism to ensure correct neuronal development.

Harmonization of L1CAM expression facilitates axon outgrowth and guidance of a motor neuron.

Brain development requires precise regulation of axon outgrowth, guidance and termination by multiple signaling and adhesion molecules. How the expression of these neurodevelopmental regulators is transcriptionally controlled is poorly understood. The Caenorhabditis elegans SMD motor neurons terminate axon outgrowth upon sexual maturity and partially retract their axons during early adulthood. Here we show that C-terminal binding protein 1 (CTBP-1), a transcriptional corepressor, is required for correct SMD axonal development. Loss of CTBP-1 causes multiple defects in SMD axon development: premature outgrowth, defective guidance, delayed termination and absence of retraction. CTBP-1 controls SMD axon guidance by repressing the expression of SAX-7, an L1 cell adhesion molecule (L1CAM). CTBP-1-regulated repression is crucial because deregulated SAX-7/L1CAM causes severely aberrant SMD axons. We found that axonal defects caused by deregulated SAX-7/L1CAM are dependent on a distinct L1CAM, called LAD-2, which itself plays a parallel role in SMD axon guidance. Our results reveal that harmonization of L1CAM expression controls the development and maturation of a single neuron.