Dissecting the Neuronal Contributions of the Lipid Regulator NHR-49 Function in Lifespan and Behavior in C. elegans
Abstract
:1. Introduction
2. Materials and Methods
2.1. C. elegans Growth and Maintenance
2.2. Plasmid Constructs and Generation of Transgenic Lines
2.3. Lifespan Assays
2.4. Scoring Embryonic Stage of Freshly Laid Eggs
2.5. Measuring Worm Speed and Path Angle
2.6. Statistical Analysis
3. Results
3.1. NHR-49 in Select Neuron Types Contribute to Lifespan
Promoter | Neuron Type | # of Neurons | Associated Function |
---|---|---|---|
dat-1 | Dopaminergic | 8 | Touch sensation [27], locomotion [28], foraging behavior [27,29], learning [30] |
tph-1 | Serotonergic | 3 | Egg-laying [31], foraging behavior [27], pharyngeal pumping [32] |
unc-25 | GABAergic | 26 | Locomotion [33], immunity [34] |
unc-17 | Cholinergic | 160 | Locomotion, male mating, egg-laying [35] |
eat-4 | Glutamatergic | 79 | Sensory signaling [36] |
3.2. NHR-49 in Neurons Contributes to Egg Production
3.3. NHR-49 in Serotonergic Neurons Contributes to Egg Laying
3.4. Reduced On-Food Speed in nhr-49 Mutants Is Not Due to NHR-49 in Any Single Tissue
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Cooper, O.; Hallett, P.; Isacson, O. Upstream lipid and metabolic systems are potential causes of Alzheimer’s disease, Parkinson’s disease and dementias. FEBS J. 2022; early view. [Google Scholar] [CrossRef]
- Antebi, A. Nuclear hormone recpetors in C. elegans. WormBook 2015, 1–49. [Google Scholar] [CrossRef] [PubMed]
- Van Gilst, M.R.; Hadjivassiliou, H.; Yamamoto, K.R. A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc. Natl. Acad. Sci. USA 2005, 102, 13496–13501. [Google Scholar] [CrossRef] [PubMed]
- Pathare, P.P.; Lin, A.; Bornfeldt, K.E.; Taubert, S.; Van Gilst, M.R. Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genet. 2012, 8, e1002645. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.; An, S.W.A.; Jung, Y.; Yamaoka, Y.; Ryu, Y.; Goh, G.Y.S.; Beigi, A.; Yang, J.S.; Jung, G.Y.; Ma, D.K.; et al. MDT-15/MED15 permits longevity at low temperature via enhancing lipidostasis and proteostasis. PLoS Biol. 2019, 17, e3000415. [Google Scholar] [CrossRef] [PubMed]
- Goh, G.Y.S.; Winter, J.J.; Bhanshali, F.; Doering, K.R.S.; Lai, R.; Lee, K.; Veal, E.A.; Taubert, S. NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting. Aging Cell 2018, 17, e12743. [Google Scholar] [CrossRef] [PubMed]
- Dasgupta, M.; Shashikanth, M.; Gupta, A.; Sandhu, A.; De, A.; Javed, S.; Singh, V. NHR-49 Transcription Factor Regulates Immunometabolic Response and Survival of Caenorhabditis elegans during Enterococcus faecalis Infection. Infect. Immun. 2020, 88, e00130-20. [Google Scholar] [CrossRef]
- Naim, N.; Amrit, F.R.G.; Ratnappan, R.; DelBuono, N.; Loose, J.A.; Ghazi, A. Cell nonautonomous roles of NHR-49 in promoting longevity and innate immunity. Aging Cell 2021, 20, e13413. [Google Scholar] [CrossRef]
- Wani, K.A.; Goswamy, D.; Taubert, S.; Ratnappan, R.; Ghazi, A.; Irazoqui, J.E. NHR-49/PPAR-alpha and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase. eLife 2021, 10, e62775. [Google Scholar] [CrossRef]
- Doering, K.R.S.; Cheng, X.; Milburn, L.; Ratnappan, R.; Ghazi, A.; Miller, D.L.; Taubert, S. Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans. eLife 2022, 11, e67911. [Google Scholar] [CrossRef]
- Ralhan, I.; Chang, C.L.; Lippincott-Schwartz, J.; Ioannou, M.S. Lipid droplets in the nervous system. J. Cell Biol. 2021, 220, e202102136. [Google Scholar] [CrossRef]
- Liu, L.; MacKenzie, K.R.; Putluri, N.; Maletic-Savatic, M.; Bellen, H.J. The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D. Cell Metab. 2017, 26, 719–737.e6. [Google Scholar] [CrossRef]
- Burkewitz, K.; Morantte, I.; Weir, H.J.M.; Yeo, R.; Zhang, Y.; Huynh, F.K.; Ilkayeva, O.R.; Hirschey, M.D.; Grant, A.R.; Mair, W.B. Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal. Cell 2015, 160, 842–855. [Google Scholar] [CrossRef]
- Altun-Gultekin, Z.; Andachi, Y.; Tsalik, E.L.; Pilgrim, D.; Kohara, Y.; Hobert, O. A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans. Development 2001, 128, 1951–1969. [Google Scholar] [CrossRef] [PubMed]
- Williams, S.L.; Lutz, S.; Charlie, N.K.; Vettel, C.; Ailion, M.; Coco, C.; Tesmer, J.J.; Jorgensen, E.M.; Wieland, T.; Miller, K.G. Trio’s Rho-specific GEF domain is the missing Galpha q effector in C. elegans. Genes Dev. 2007, 21, 2731–2746. [Google Scholar] [CrossRef]
- Lee, R.Y.; Sawin, E.R.; Chalfie, M.; Horvitz, H.R.; Avery, L. EAT-4, a homolog of a mammalian sodium-dependent inorganic phosphate cotransporter, is necessary for glutamatergic neurotransmission in Caenorhabditis elegans. J. Neurosci. 1999, 19, 159–167. [Google Scholar] [CrossRef]
- Pocock, R.; Hobert, O. Hypoxia activates a latent circuit for processing gustatory information in C. elegans. Nat. Neurosci. 2010, 13, 610–614. [Google Scholar] [CrossRef] [PubMed]
- Nass, R.; Hall, D.H.; Miller, D.M., 3rd; Blakely, R.D. Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2002, 99, 3264–3269. [Google Scholar] [CrossRef]
- Eastman, C.; Horvitz, H.R.; Jin, Y. Coordinated transcriptional regulation of the unc-25 glutamic acid decarboxylase and the unc-47 GABA vesicular transporter by the Caenorhabditis elegans UNC-30 homeodomain protein. J. Neurosci. 1999, 19, 6225–6234. [Google Scholar] [CrossRef]
- Ringstad, N.; Horvitz, H.R. FMRFamide neuropeptides and acetylcholine synergistically inhibit egg-laying by C. elegans. Nat. Neurosci. 2008, 11, 1168–1176. [Google Scholar] [CrossRef]
- de Bono, M.; Bargmann, C.I. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 1998, 94, 679–689. [Google Scholar] [CrossRef]
- Nussbaum-Krammer, C.I.; Neto, M.F.; Brielmann, R.M.; Pedersen, J.S.; Morimoto, R.I. Investigating the spreading and toxicity of prion-like proteins using the metazoan model organism C. elegans. J. Vis. Exp. 2015, 95, 52321. [Google Scholar] [CrossRef]
- Han, S.K.; Lee, D.; Lee, H.; Kim, D.; Son, H.G.; Yang, J.S.; Lee, S.V.; Kim, S. OASIS 2: Online application for survival analysis 2 with features for the analysis of maximal lifespan and healthspan in aging research. Oncotarget 2016, 7, 56147–56152. [Google Scholar] [CrossRef]
- Wang, H.; Liu, J.; Gharib, S.; Chai, C.M.; Schwarz, E.M.; Pokala, N.; Sternberg, P.W. cGAL, a temperature-robust GAL4-UAS system for Caenorhabditis elegans. Nat. Methods 2017, 14, 145–148. [Google Scholar] [CrossRef]
- Murata, D.; Nomura, K.H.; Dejima, K.; Mizuguchi, S.; Kawasaki, N.; Matsuishi-Nakajima, Y.; Ito, S.; Gengyo-Ando, K.; Kage-Nakadai, E.; Mitani, S.; et al. GPI-anchor synthesis is indispensable for the germline development of the nematode Caenorhabditis elegans. Mol. Biol. Cell 2012, 23, 982–995. [Google Scholar] [CrossRef] [PubMed]
- Munoz-Jimenez, C.; Ayuso, C.; Dobrzynska, A.; Torres-Mendez, A.; Ruiz, P.C.; Askjaer, P. An Efficient FLP-Based Toolkit for Spatiotemporal Control of Gene Expression in Caenorhabditis elegans. Genetics 2017, 206, 1763–1778. [Google Scholar] [CrossRef] [PubMed]
- Sawin, E.R.; Ranganathan, R.; Horvitz, H.R. C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 2000, 26, 619–631. [Google Scholar] [CrossRef] [PubMed]
- Omura, D.T.; Clark, D.A.; Samuel, A.D.; Horvitz, H.R. Dopamine signaling is essential for precise rates of locomotion by C. elegans. PLoS ONE 2012, 7, e38649. [Google Scholar] [CrossRef]
- Hills, T.; Brockie, P.J.; Maricq, A.V. Dopamine and glutamate control area-restricted search behavior in Caenorhabditis elegans. J. Neurosci. 2004, 24, 1217–1225. [Google Scholar] [CrossRef] [PubMed]
- Sanyal, S.; Wintle, R.F.; Kindt, K.S.; Nuttley, W.M.; Arvan, R.; Fitzmaurice, P.; Bigras, E.; Merz, D.C.; Hebert, T.E.; van der Kooy, D.; et al. Dopamine modulates the plasticity of mechanosensory responses in Caenorhabditis elegans. EMBO J. 2004, 23, 473–482. [Google Scholar] [CrossRef] [PubMed]
- Weinshenker, D.; Garriga, G.; Thomas, J.H. Genetic and pharmacological analysis of neurotransmitters controlling egg laying in C. elegans. J. Neurosci. 1995, 15, 6975–6985. [Google Scholar] [CrossRef]
- Segalat, L.; Elkes, D.A.; Kaplan, J.M. Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans. Science 1995, 267, 1648–1651. [Google Scholar] [CrossRef]
- Jorgensen, E.M. GABA. WormBook 2005, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Zheng, Z.; Zhang, X.; Liu, J.; He, P.; Zhang, S.; Zhang, Y.; Gao, J.; Yang, S.; Kang, N.; Afridi, M.I.; et al. GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2021, 118, e2021063118. [Google Scholar] [CrossRef]
- Rand, J.B. Acetylcholine. WormBook 2006, 1–21. [Google Scholar] [CrossRef] [PubMed]
- Choi, J.H.; Horowitz, L.B.; Ringstad, N. Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit. Nat. Commun. 2021, 12, 6334. [Google Scholar] [CrossRef] [PubMed]
- Schafer, W.R. Egg-laying. WormBook 2005, 1–7. [Google Scholar] [CrossRef]
- Medrano, E.; Collins, K.M. Muscle-directed mechanosensory feedback activates egg-laying circuit activity and behavior in Caenorhabditis elegans. Curr. Biol. 2023, 33, 2330–2339.e8. [Google Scholar] [CrossRef]
- Gray, J.M.; Hill, J.J.; Bargmann, C.I. A circuit for navigation in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2005, 102, 3184–3191. [Google Scholar] [CrossRef]
- Pradhan, S.; Quilez, S.; Homer, K.; Hendricks, M. Environmental Programming of Adult Foraging Behavior in C. elegans. Curr. Biol. 2019, 29, 2867–2879.e4. [Google Scholar] [CrossRef]
- Shtonda, B.B.; Avery, L. Dietary choice behavior in Caenorhabditis elegans. J. Exp. Biol. 2006, 209, 89–102. [Google Scholar] [CrossRef]
- Fujiwara, M.; Sengupta, P.; McIntire, S.L. Regulation of body size and behavioral state of C. elegans by sensory perception and the EGL-4 cGMP-dependent protein kinase. Neuron 2002, 36, 1091–1102. [Google Scholar] [CrossRef]
- Ben Arous, J.; Laffont, S.; Chatenay, D. Molecular and sensory basis of a food related two-state behavior in C. elegans. PLoS ONE 2009, 4, e7584. [Google Scholar] [CrossRef] [PubMed]
- Ratnappan, R.; Amrit, F.R.; Chen, S.W.; Gill, H.; Holden, K.; Ward, J.; Yamamoto, K.R.; Olsen, C.P.; Ghazi, A. Germline signals deploy NHR-49 to modulate fatty-acid beta-oxidation and desaturation in somatic tissues of C. elegans. PLoS Genet. 2014, 10, e1004829. [Google Scholar] [CrossRef] [PubMed]
- Cai, H.; Cong, W.N.; Ji, S.; Rothman, S.; Maudsley, S.; Martin, B. Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Curr. Alzheimer Res. 2012, 9, 5–17. [Google Scholar] [CrossRef] [PubMed]
- Podolsky, S.; Leopold, N.A.; Sax, D.S. Increased frequency of diabetes mellitus in patients with Huntington’s chorea. Lancet 1972, 1, 1356–1358. [Google Scholar] [CrossRef] [PubMed]
- Fielenbach, N.; Antebi, A. C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 2008, 22, 2149–2165. [Google Scholar] [CrossRef] [PubMed]
- Hodgkin, J.; Barnes, T.M. More is not better: Brood size and population growth in a self-fertilizing nematode. Proc. Biol. Sci. 1991, 246, 19–24. [Google Scholar] [CrossRef]
- Emtage, L.; Aziz-Zaman, S.; Padovan-Merhar, O.; Horvitz, H.R.; Fang-Yen, C.; Ringstad, N. IRK-1 potassium channels mediate peptidergic inhibition of Caenorhabditis elegans serotonin neurons via a G(o) signaling pathway. J. Neurosci. 2012, 32, 16285–16295. [Google Scholar] [CrossRef]
- Huang, K.M.; Cosman, P.; Schafer, W.R. Automated detection and analysis of foraging behavior in Caenorhabditis elegans. J. Neurosci. Methods 2008, 171, 153–164. [Google Scholar] [CrossRef]
- Avery, L.; You, Y.J. C. elegans feeding. WormBook 2012. [Google Scholar] [CrossRef]
- Prahlad, V.; Morimoto, R.I. Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins. Proc. Natl. Acad. Sci. USA 2011, 108, 14204–14209. [Google Scholar] [CrossRef]
- van Oosten-Hawle, P.; Morimoto, R.I. Organismal proteostasis: Role of cell-nonautonomous regulation and transcellular chaperone signaling. Genes Dev. 2014, 28, 1533–1543. [Google Scholar] [CrossRef] [PubMed]
- Taylor, R.C.; Dillin, A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 2013, 153, 1435–1447. [Google Scholar] [CrossRef]
- Chauve, L.; Hodge, F.; Murdoch, S.; Masoudzadeh, F.; Mann, H.J.; Lopez-Clavijo, A.F.; Okkenhaug, H.; West, G.; Sousa, B.C.; Segonds-Pichon, A.; et al. Neuronal HSF-1 coordinates the propagation of fat desaturation across tissues to enable adaptation to high temperatures in C. elegans. PLoS Biol. 2021, 19, e3001431. [Google Scholar] [CrossRef]
- Zullo, J.M.; Drake, D.; Aron, L.; O’Hern, P.; Dhamne, S.C.; Davidsohn, N.; Mao, C.A.; Klein, W.H.; Rotenberg, A.; Bennett, D.A.; et al. Regulation of lifespan by neural excitation and REST. Nature 2019, 574, 359–364. [Google Scholar] [CrossRef] [PubMed]
- Ozbey, N.P.; Imanikia, S.; Krueger, C.; Hardege, I.; Morud, J.; Sheng, M.; Schafer, W.R.; Casanueva, M.O.; Taylor, R.C. Tyramine Acts Downstream of Neuronal XBP-1s to Coordinate Inter-tissue UPR(ER) Activation and Behavior in C. elegans. Dev. Cell 2020, 55, 754–770.e6. [Google Scholar] [CrossRef] [PubMed]
- Berendzen, K.M.; Durieux, J.; Shao, L.W.; Tian, Y.; Kim, H.E.; Wolff, S.; Liu, Y.; Dillin, A. Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis. Cell 2016, 166, 1553–1563.e10. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Wu, X.; Chen, P.; Liu, L.; Xin, N.; Tian, Y.; Dillin, A. The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling. Cell 2018, 174, 870–883.e17. [Google Scholar] [CrossRef]
- Savini, M.; Folick, A.; Lee, Y.T.; Jin, F.; Cuevas, A.; Tillman, M.C.; Duffy, J.D.; Zhao, Q.; Neve, I.A.; Hu, P.W.; et al. Lysosome lipid signalling from the periphery to neurons regulates longevity. Nat. Cell Biol. 2022, 24, 906–916. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kwon, S.; Park, K.-S.; Yoon, K.-h. Dissecting the Neuronal Contributions of the Lipid Regulator NHR-49 Function in Lifespan and Behavior in C. elegans. Life 2023, 13, 2346. https://doi.org/10.3390/life13122346
Kwon S, Park K-S, Yoon K-h. Dissecting the Neuronal Contributions of the Lipid Regulator NHR-49 Function in Lifespan and Behavior in C. elegans. Life. 2023; 13(12):2346. https://doi.org/10.3390/life13122346
Chicago/Turabian StyleKwon, Saebom, Kyu-Sang Park, and Kyoung-hye Yoon. 2023. "Dissecting the Neuronal Contributions of the Lipid Regulator NHR-49 Function in Lifespan and Behavior in C. elegans" Life 13, no. 12: 2346. https://doi.org/10.3390/life13122346
APA StyleKwon, S., Park, K. -S., & Yoon, K. -h. (2023). Dissecting the Neuronal Contributions of the Lipid Regulator NHR-49 Function in Lifespan and Behavior in C. elegans. Life, 13(12), 2346. https://doi.org/10.3390/life13122346