mTORC1 pathway activity biases cell fate choice.
Dictyostelium discoideum
Cell fate choice
Rapamycin
Set1
mTORC1
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 Sep 2024
06 Sep 2024
Historique:
received:
15
05
2024
accepted:
27
08
2024
medline:
7
9
2024
pubmed:
7
9
2024
entrez:
6
9
2024
Statut:
epublish
Résumé
Pluripotent stem cells can differentiate into distinct cell types but the intracellular pathways controlling cell fate choice are not well understood. The social amoeba Dictyostelium discoideum is a simplified system to study choice preference as proliferating amoebae enter a developmental cycle upon starvation and differentiate into two major cell types, stalk and spores, organised in a multicellular fruiting body. Factors such as acidic vesicle pH predispose amoebae to one fate. Here we show that the mechanistic target of rapamycin complex 1 (mTORC1) pathway has a role in cell fate bias in Dictyostelium. Inhibiting the mTORC1 pathway activity by disruption of Rheb (activator Ras homolog enriched in brain), or treatment with the mTORC1 inhibitor rapamycin prior to development, biases cells to a spore cell fate. Conversely activation of the pathway favours stalk cell differentiation. The Set1 histone methyltransferase, responsible for histone H3 lysine4 methylation, in Dictyostelium cells regulates transcription at the onset of development. Disruption of Set1 leads to high mTORC1 pathway activity and stalk cell predisposition. The ability of the mTORC1 pathway to regulate cell fate bias of cells undergoing differentiation offers a potential target to increase the efficiency of stem cell differentiation into a particular cell type.
Identifiants
pubmed: 39242621
doi: 10.1038/s41598-024-71298-2
pii: 10.1038/s41598-024-71298-2
doi:
Substances chimiques
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Sirolimus
W36ZG6FT64
Protozoan Proteins
0
Monomeric GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
20832Subventions
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/M000834/1
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
Références
Katoh, M., Chen, G., Roberge, E., Shaulsky, G. & Kuspa, A. Developmental commitment in Dictyostelium discoideum. Eukaryot Cell 6, 2038–2045. https://doi.org/10.1128/ec.00223-07 (2007).
doi: 10.1128/ec.00223-07
pubmed: 17905919
pmcid: 2168402
Loomis, W. F. Cell signaling during development of Dictyostelium. Dev. Biol. 391, 1–16. https://doi.org/10.1016/j.ydbio.2014.04.001 (2014).
doi: 10.1016/j.ydbio.2014.04.001
pubmed: 24726820
pmcid: 4075484
Thompson, C. R. & Kay, R. R. Cell-fate choice in Dictyostelium: intrinsic biases modulate sensitivity to DIF signaling. Dev. Biol. 227, 56–64. https://doi.org/10.1006/dbio.2000.9877 (2000).
doi: 10.1006/dbio.2000.9877
pubmed: 11076676
Strmecki, L., Greene, D. M. & Pears, C. J. Developmental decisions in Dictyostelium discoideum. Dev. Biol. 284, 25–36. https://doi.org/10.1016/j.ydbio.2005.05.011 (2005).
doi: 10.1016/j.ydbio.2005.05.011
pubmed: 15964562
Kay, R. R., Flatman, P. & Thompson, C. R. DIF signalling and cell fate. Semin Cell Dev. Biol. 10, 577–585. https://doi.org/10.1006/scdb.1999.0341 (1999).
doi: 10.1006/scdb.1999.0341
pubmed: 10706822
Thompson, C. R. & Kay, R. R. The role of DIF-1 signaling in Dictyostelium development. Mol. Cell 6, 1509–1514. https://doi.org/10.1016/s1097-2765(00)00147-7 (2000).
doi: 10.1016/s1097-2765(00)00147-7
pubmed: 11163223
Gomer, R. H. & Ammann, R. R. A cell-cycle phase-associated cell-type choice mechanism monitors the cell cycle rather than using an independent timer. Dev. Biol. 174, 82–91. https://doi.org/10.1006/dbio.1996.0053 (1996).
doi: 10.1006/dbio.1996.0053
pubmed: 8626023
Gross, J. D., Bradbury, J., Kay, R. R. & Peacey, M. J. Intracellular pH and the control of cell differentiation in Dictyostelium discoideum. Nature 303, 244–245. https://doi.org/10.1038/303244a0 (1983).
doi: 10.1038/303244a0
pubmed: 6843673
Hiraoka, H. et al. Intracellular ATP levels influence cell fates in Dictyostelium discoideum differentiation. Genes Cells 25, 312–326. https://doi.org/10.1111/gtc.12763 (2020).
doi: 10.1111/gtc.12763
pubmed: 32125743
pmcid: 7318147
Leach, C. K., Ashworth, J. M. & Garrod, D. R. Cell sorting out during the differentiation of mixtures of metabolically distinct populations of Dictyostelium discoideum. J. Embryol. Exp. Morphol. 29, 647–661 (1973).
pubmed: 4736935
Azhar, M., Manogaran, P. S., Kennady, P. K., Pande, G. & Nanjundiah, V. A Ca(2+)-dependent early functional heterogeneity in amoebae of Dictyostelium discoideum, revealed by flow cytometry. Exp. Cell Res. 227, 344–351. https://doi.org/10.1006/excr.1996.0283 (1996).
doi: 10.1006/excr.1996.0283
pubmed: 8831572
Traynor, D., Milne, J. L., Insall, R. H. & Kay, R. R. Ca(2+) signalling is not required for chemotaxis in Dictyostelium. EMBO J. 19, 4846–4854. https://doi.org/10.1093/emboj/19.17.4846 (2000).
doi: 10.1093/emboj/19.17.4846
pubmed: 10970875
pmcid: 302083
Chang, F. S. et al. A two-pore channel protein required for regulating mTORC1 activity on starvation. BMC Biol 18, 8. https://doi.org/10.1186/s12915-019-0735-4 (2020).
doi: 10.1186/s12915-019-0735-4
pubmed: 31969153
pmcid: 6977259
Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15, 155–162. https://doi.org/10.1038/nrm3757 (2014).
doi: 10.1038/nrm3757
pubmed: 24556838
Wolfson, R. L. & Sabatini, D. M. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab 26, 301–309. https://doi.org/10.1016/j.cmet.2017.07.001 (2017).
doi: 10.1016/j.cmet.2017.07.001
pubmed: 28768171
pmcid: 5560103
Patel, C. H. & Powell, J. D. Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr. Opin. Immunol. 46, 82–88. https://doi.org/10.1016/j.coi.2017.04.006 (2017).
doi: 10.1016/j.coi.2017.04.006
pubmed: 28521236
pmcid: 5554728
Zeng, H. et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45, 540–554. https://doi.org/10.1016/j.immuni.2016.08.017 (2016).
doi: 10.1016/j.immuni.2016.08.017
pubmed: 27637146
pmcid: 5050556
Zheng, Y. et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J. Immunol. 178, 2163–2170. https://doi.org/10.4049/jimmunol.178.4.2163 (2007).
doi: 10.4049/jimmunol.178.4.2163
pubmed: 17277121
Chen, T. et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10, 908–911. https://doi.org/10.1111/j.1474-9726.2011.00722.x (2011).
doi: 10.1111/j.1474-9726.2011.00722.x
pubmed: 21615676
Sempou, E. et al. Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR. Nat. Commun. 13, 6681. https://doi.org/10.1038/s41467-022-34363-w (2022).
doi: 10.1038/s41467-022-34363-w
pubmed: 36335122
pmcid: 9637099
Hobbs, R. M. et al. Distinct germline progenitor subsets defined through Tsc2-mTORC1 signaling. EMBO Rep 16, 467–480. https://doi.org/10.15252/embr.201439379 (2015).
doi: 10.15252/embr.201439379
pubmed: 25700280
pmcid: 4388613
Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 510, 393–396. https://doi.org/10.1038/nature13255 (2014).
doi: 10.1038/nature13255
pubmed: 24870234
pmcid: 4065227
Steinberg, G. R. & Hardie, D. G. New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 24, 255–272. https://doi.org/10.1038/s41580-022-00547-x (2023).
doi: 10.1038/s41580-022-00547-x
pubmed: 36316383
Lee, J. H. et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020. https://doi.org/10.1038/nature05828 (2007).
doi: 10.1038/nature05828
pubmed: 17486097
Yang, H. et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368–373. https://doi.org/10.1038/nature25023 (2017).
doi: 10.1038/nature25023
pubmed: 29236692
pmcid: 5750076
Jaiswal, P. et al. Integrated actions of mTOR complexes 1 and 2 for growth and development of Dictyostelium. Int. J. Dev. Biol. 63, 521–527. https://doi.org/10.1387/ijdb.190245ak (2019).
doi: 10.1387/ijdb.190245ak
pubmed: 31840789
Jaiswal, P. & Kimmel, A. R. mTORC1/AMPK responses define a core gene set for developmental cell fate switching. BMC Biol 17, 58. https://doi.org/10.1186/s12915-019-0673-1 (2019).
doi: 10.1186/s12915-019-0673-1
pubmed: 31319820
pmcid: 6637605
Swer, P. B., Mishra, H., Lohia, R. & Saran, S. Overexpression of TOR (target of rapamycin) inhibits cell proliferation in Dictyostelium discoideum. J. Basic Microbiol. 56, 510–519. https://doi.org/10.1002/jobm.201500313 (2016).
doi: 10.1002/jobm.201500313
pubmed: 26460541
Swer, P. B., Bhadoriya, P. & Saran, S. Analysis of Rheb in the cellular slime mold Dictyostelium discoideum: cellular localization, spatial expression and overexpression. J. Biosci. 39, 75–84. https://doi.org/10.1007/s12038-013-9405-9 (2014).
doi: 10.1007/s12038-013-9405-9
pubmed: 24499792
Maurya, R., Kumar, R. & Saran, S. Dictyostelium AMPK alpha regulates aggregate size and cell-type patterning. Open Biol 7, 170055. https://doi.org/10.1098/rsob.170055 (2017).
doi: 10.1098/rsob.170055
pubmed: 28701378
pmcid: 5541345
Maurya, R., Kumar, R. & Saran, S. AMPKα promotes basal autophagy induction in Dictyostelium discoideum. J. Cell. Physiol. 235, 4941–4953. https://doi.org/10.1002/jcp.29373 (2020).
doi: 10.1002/jcp.29373
pubmed: 31680241
Chubb, J. R. et al. Developmental timing in Dictyostelium is regulated by the Set1 histone methyltransferase. Dev Biol 292, 519–532. https://doi.org/10.1016/j.ydbio.2005.12.054 (2006).
doi: 10.1016/j.ydbio.2005.12.054
pubmed: 16469305
Davies, L., Satre, M., Martin, J. B. & Gross, J. D. The target of ammonia action in dictyostelium. Cell 75, 321–327. https://doi.org/10.1016/0092-8674(93)80073-n (1993).
doi: 10.1016/0092-8674(93)80073-n
pubmed: 8402915
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976. https://doi.org/10.1016/j.cell.2017.02.004 (2017).
doi: 10.1016/j.cell.2017.02.004
pubmed: 28283069
pmcid: 5394987
Smith, P. K., Sen, M. G., Fisher, P. R. & Annesley, S. J. Modelling of neuronal ceroid lipofuscinosis Type 2 in Dictyostelium discoideum suggests that cytopathological outcomes result from altered TOR signalling. Cells https://doi.org/10.3390/cells8050469 (2019).
doi: 10.3390/cells8050469
pubmed: 31766580
pmcid: 6952969
Gruenheit, N. et al. Cell cycle heterogeneity can generate robust cell type proportioning. Dev. Cell 47, 494-508 e494. https://doi.org/10.1016/j.devcel.2018.09.023 (2018).
doi: 10.1016/j.devcel.2018.09.023
pubmed: 30473004
pmcid: 6251973
Buttery, N. J., Rozen, D. E., Wolf, J. B. & Thompson, C. R. Quantification of social behavior in D. discoideum reveals complex fixed and facultative strategies. Curr. Biol. 19, 1373–1377. https://doi.org/10.1016/j.cub.2009.06.058 (2009).
doi: 10.1016/j.cub.2009.06.058
pubmed: 19631539
Gross, J. D. & Pears, C. J. Possible involvement of the nutrient and energy sensors mTORC1 and AMPK in cell fate diversification in a non-metazoan organism. Front. Cell Dev. Biol. 9, 758317. https://doi.org/10.3389/fcell.2021.758317 (2021).
doi: 10.3389/fcell.2021.758317
pubmed: 34820379
pmcid: 8606421
Sugden, C., Urbaniak, M. D., Araki, T. & Williams, J. G. The Dictyostelium prestalk inducer differentiation-inducing factor-1 (DIF-1) triggers unexpectedly complex global phosphorylation changes. Mol. Biol. Cell 26, 805–820. https://doi.org/10.1091/mbc.E14-08-1319 (2015).
doi: 10.1091/mbc.E14-08-1319
pubmed: 25518940
pmcid: 4325849
Rathore, M., Thakur, A. & Saran, S. Deletion of Dictyostelium tpc2 gene forms multi-tipped structures, regulates autophagy and cell-type patterning. Biol. Cell https://doi.org/10.1111/boc.202300067 (2024).
doi: 10.1111/boc.202300067
pubmed: 38537110
Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338. https://doi.org/10.1038/nri3198 (2012).
doi: 10.1038/nri3198
pubmed: 22517423
pmcid: 3417069
Blagih, J. et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42, 41–54. https://doi.org/10.1016/j.immuni.2014.12.030 (2015).
doi: 10.1016/j.immuni.2014.12.030
pubmed: 25607458
Suvorova, I. I., Knyazeva, A. R., Petukhov, A. V., Aksenov, N. D. & Pospelov, V. A. Resveratrol enhances pluripotency of mouse embryonic stem cells by activating AMPK/Ulk1 pathway. Cell Death Discov. 5, 61. https://doi.org/10.1038/s41420-019-0137-y (2019).
doi: 10.1038/s41420-019-0137-y
pubmed: 30729040
pmcid: 6361884
Hussein, A. M. et al. Metabolic control over mTOR-dependent diapause-like state. Dev. Cell 52, 236-250.e237. https://doi.org/10.1016/j.devcel.2019.12.018 (2020).
doi: 10.1016/j.devcel.2019.12.018
pubmed: 31991105
pmcid: 7204393
Rosel, D. et al. TOR complex 2 (TORC2) in Dictyostelium suppresses phagocytic nutrient capture independently of TORC1-mediated nutrient sensing. J. Cell Sci. 125, 37–48. https://doi.org/10.1242/jcs.077040 (2012).
doi: 10.1242/jcs.077040
pubmed: 22266904
pmcid: 3269021
Warren, E. C. et al. Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling. Proc. Natl. Acad. Sci. U S A 117, 23617–23625. https://doi.org/10.1073/pnas.2008980117 (2020).
doi: 10.1073/pnas.2008980117
pubmed: 32879008
pmcid: 7519326
Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945. https://doi.org/10.1101/gad.1212704 (2004).
doi: 10.1101/gad.1212704
pubmed: 15314020
Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307–318. https://doi.org/10.1038/nrm2672 (2009).
doi: 10.1038/nrm2672
pubmed: 19339977
Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797–806. https://doi.org/10.1016/s0960-9822(03)00329-4 (2003).
doi: 10.1016/s0960-9822(03)00329-4
pubmed: 12747827
Goldberg, J. M. et al. The dictyostelium kinome–analysis of the protein kinases from a simple model organism. PLoS Genet 2, e38. https://doi.org/10.1371/journal.pgen.0020038 (2006).
doi: 10.1371/journal.pgen.0020038
pubmed: 16596165
pmcid: 1420674
Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nat. Rev. Genet. 12, 7–18. https://doi.org/10.1038/nrg2905 (2011).
doi: 10.1038/nrg2905
pubmed: 21116306
Huang, L. Y., Hsu, D. W. & Pears, C. J. Methylation-directed acetylation of histone H3 regulates developmental sensitivity to histone deacetylase inhibition. Nucl. Acids Res 49, 3781–3795. https://doi.org/10.1093/nar/gkab154 (2021).
doi: 10.1093/nar/gkab154
pubmed: 33721015
pmcid: 8053100
Kuwana, S., Senoo, H., Sawai, S. & Fukuzawa, M. A novel, lineage-primed prestalk cell subtype involved in the morphogenesis of D. discoideum. Dev. Biol. 416, 286–299. https://doi.org/10.1016/j.ydbio.2016.06.032 (2016).
doi: 10.1016/j.ydbio.2016.06.032
pubmed: 27373689
Chattwood, A. et al. Developmental lineage priming in Dictyostelium by heterogeneous Ras activation. Elife 2, e01067. https://doi.org/10.7554/eLife.01067 (2013).
doi: 10.7554/eLife.01067
pubmed: 24282234
pmcid: 3838634
Gaudet, P., Pilcher, K. E., Fey, P. & Chisholm, R. L. Transformation of Dictyostelium discoideum with plasmid DNA. Nat. Protoc. 2, 1317–1324. https://doi.org/10.1038/nprot.2007.179 (2007).
doi: 10.1038/nprot.2007.179
pubmed: 17545968
Ostrowski, E. A., Katoh, M., Shaulsky, G., Queller, D. C. & Strassmann, J. E. Kin discrimination increases with genetic distance in a social amoeba. PLoS Biol. 6, e287. https://doi.org/10.1371/journal.pbio.0060287 (2008).
doi: 10.1371/journal.pbio.0060287
pubmed: 19067487
pmcid: 2586364
Thompson, C. R., Fu, Q., Buhay, C., Kay, R. R. & Shaulsky, G. A bZIP/bRLZ transcription factor required for DIF signaling in Dictyostelium. Development 131, 513–523. https://doi.org/10.1242/dev.00939 (2004).
doi: 10.1242/dev.00939
pubmed: 14729573
Jermyn, K. A. & Williams, J. G. An analysis of culmination in dictyostelium using prestalk and stalk-specific cell autonomous markers. Development 111, 779–787 (1991).
doi: 10.1242/dev.111.3.779
pubmed: 1879341
Vinet, A. F. et al. Initiation of multicellular differentiation in Dictyostelium discoideum is regulated by coronin A. Mol. Biol. Cell 25, 688–701. https://doi.org/10.1091/mbc.E13-04-0219 (2014).
doi: 10.1091/mbc.E13-04-0219
pubmed: 24403600
pmcid: 3937094
Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative CT method. Nat. Protoc. 3, 1101–1108. https://doi.org/10.1038/nprot.2008.73 (2008).
doi: 10.1038/nprot.2008.73
pubmed: 18546601
Sekine, R., Kawata, T. & Muramoto, T. CRISPR/Cas9 mediated targeting of multiple genes in Dictyostelium. Sci. Rep 8, 8471. https://doi.org/10.1038/s41598-018-26756-z (2018).
doi: 10.1038/s41598-018-26756-z
pubmed: 29855514
pmcid: 5981456
Hsu, D. W., Chubb, J. R., Muramoto, T., Pears, C. J. & Mahadevan, L. C. Dynamic acetylation of lysine-4-trimethylated histone H3 and H3 variant biology in a simple multicellular eukaryote. Nucleic Acids Res 40, 7247–7256. https://doi.org/10.1093/nar/gks367 (2012).
doi: 10.1093/nar/gks367
pubmed: 22600736
pmcid: 3424546
Davidson, A. J., King, J. S. & Insall, R. H. The use of streptavidin conjugates as immunoblot loading controls and mitochondrial markers for use with Dictyostelium discoideum. Biotechniques 55, 39–41. https://doi.org/10.2144/000114054 (2013).
doi: 10.2144/000114054
pubmed: 23834384