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SRF and SRFΔ5 Splicing Isoform Recruit Corepressor LSD1/KDM1A Modifying Structural Neuroplasticity and Environmental Stress Response

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Abstract

Ten to 20% of western countries population suffers from major depression disorder (MDD). Stressful life events represent the main environmental risk factor contributing to the onset of MDD and other stress-related neuropsychiatric disorders. In this regard, investigating brain physiology of stress response underlying the remarkable individual variability in terms of behavioral outcome may uncover stress-vulnerability pathways as a source of candidate targets for conceptually new antidepressant treatments. Serum response factor (SRF) has been addressed as a stress transducer via promoting inherent experience-induced Immediate Early Genes (IEGs) expression in neurons. However, in resting conditions, SRF also represents a transcriptional repressor able to assemble the core LSD1/CoREST/HDAC2 corepressor complex, including demethylase and deacetylase activities. We here show that dominant negative SRF splicing isoform lacking most part of the transactivation domain, namely SRFΔ5, owes its transcriptional repressive behavior to the ability of assembling LSD1/CoREST/HDAC2 corepressor complex meanwhile losing its affinity for transcription-permissive cofactor ELK1. SRFΔ5 is highly expressed in the brain and developmentally regulated. In the light of its activity as negative modulator of dendritic spine density, SRFΔ5 increase along with brain maturation suggests a role in synaptic pruning. Upon acute psychosocial stress, SRFΔ5 isoform transiently increases its levels. Remarkably, when stress is chronically repeated, a different picture occurs where SRF protein becomes stably upregulated in vulnerable mice but not in resilient animals. These data suggest a role for SRFΔ5 that is restricted to acute stress response, while positive modulation of SRF during chronic stress matches the criteria for stress-vulnerability hallmark.

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References

  1. McEwen BS, Eiland L, Hunter RG, Miller MM (2012) Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology 62:3–12

    CAS  PubMed  Google Scholar 

  2. Bagot RC, Labonté B, Peña CJ, Nestler EJ (2014) Epigenetic signaling in psychiatric disorders: stress and depression. Dialogues Clin Neurosci 16:281–295

    PubMed  PubMed Central  Google Scholar 

  3. Sun H, Kennedy PJ, Nestler EJ (2013) Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38:124–137

    CAS  PubMed  Google Scholar 

  4. McEwen BS, Nasca C, Gray JD (2016) Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41:3–23

    CAS  PubMed  Google Scholar 

  5. Golden SA, Covington HE, Berton O, Russo SJ (2011) A standardized protocol for repeated social defeat stress in mice. Nat Protoc 6:1183–1191

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Chattarji S, Tomar A, Suvrathan A, Ghosh S, Rahman MM (2015) Neighborhood matters: divergent patterns of stress-induced plasticity across the brain. Nat Neurosci 18:1364–1375

    CAS  PubMed  Google Scholar 

  7. Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62:63–77

    CAS  PubMed  Google Scholar 

  8. Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, Chen B, Hen R (2018) Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature 559:98–102

    CAS  PubMed  PubMed Central  Google Scholar 

  9. McEwen BS, Gray J, Nasca C (2015) Recognizing resilience: learning from the effects of stress on the brain. Neurobiol Stress 1:1–11

    PubMed  Google Scholar 

  10. Bagot RC, Parise EM, Peña CJ, Zhang HX, Maze I, Chaudhury D, Persaud B, Cachope R et al (2015) Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun 6:7062

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shin S, Kwon O, Kang JI, Kwon S, Oh S, Choi J, Kim CH, Kim DG (2015) mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress. Nat Neurosci 18:1017–1024

    CAS  PubMed  Google Scholar 

  12. Rusconi F, Battaglioli E (2018) Acute stress-induced epigenetic modulations and their potential protective role toward depression. Front Mol Neurosci 11:184

    PubMed  PubMed Central  Google Scholar 

  13. Vialou V, Maze I, Renthal W, LaPlant QC, Watts EL, Mouzon E, Ghose S, Tamminga CA et al (2010) Serum response factor promotes resilience to chronic social stress through the induction of DeltaFosB. J Neurosci 30:14585–14592

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zimprich A, Mroz G, Meyer Zu Reckendorf C, Anastasiadou S, Förstner P, Garrett L, Hölter SM, Becker L et al (2017) Serum response factor (SRF) ablation interferes with acute stress-associated immediate and long-term coping mechanisms. Mol Neurobiol 54(10):8242–8262

    PubMed  Google Scholar 

  15. Saunderson EA, Spiers H, Mifsud KR, Gutierrez-Mecinas M, Trollope AF, Shaikh A, Mill J, Reul JM (2016) Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus. Proc Natl Acad Sci U S A 113:4830–4835

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ramanan N, Shen Y, Sarsfield S, Lemberger T, Schütz G, Linden DJ, Ginty DD (2005) SRF mediates activity-induced gene expression and synaptic plasticity but not neuronal viability. Nat Neurosci 8:759–767

    CAS  PubMed  Google Scholar 

  17. Knöll B, Nordheim A (2009) Functional versatility of transcription factors in the nervous system: the SRF paradigm. Trends Neurosci 32:432–442

    PubMed  Google Scholar 

  18. Rusconi F, Grillo B, Ponzoni L, Bassani S, Toffolo E, Paganini L, Mallei A, Braida D et al (2016) LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior. Proc Natl Acad Sci U S A 113:3651–3656

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rusconi F, Grillo B, Toffolo E, Mattevi A, Battaglioli E (2017) NeuroLSD1: splicing-generated epigenetic enhancer of neuroplasticity. Trends Neurosci 40:28–38

    CAS  PubMed  Google Scholar 

  21. Johansen FE, Prywes R (1993) Identification of transcriptional activation and inhibitory domains in serum response factor (SRF) by using GAL4-SRF constructs. Mol Cell Biol 13:4640–4647

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Shaw PE, Frasch S, Nordheim A (1989) Repression of c-fos transcription is mediated through p67SRF bound to the SRE. EMBO J 8:2567–2574

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Liao J, Hodge C, Meyer D, Ho PS, Rosenspire K, Schwartz J (1997) Growth hormone regulates ternary complex factors and serum response factor associated with the c-fos serum response element. J Biol Chem 272:25951–25958

    CAS  PubMed  Google Scholar 

  24. Kalita K, Kharebava G, Zheng JJ, Hetman M (2006) Role of megakaryoblastic acute leukemia-1 in ERK1/2-dependent stimulation of serum response factor-driven transcription by BDNF or increased synaptic activity. J Neurosci 26:10020–10032

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kalita K, Kuzniewska B, Kaczmarek L (2012) MKLs: co-factors of serum response factor (SRF) in neuronal responses. Int J Biochem Cell Biol 44:1444–1447

    CAS  PubMed  Google Scholar 

  26. Belaguli NS, Zhou W, Trinh TH, Majesky MW, Schwartz RJ (1999) Dominant negative murine serum response factor: alternative splicing within the activation domain inhibits transactivation of serum response factor binding targets. Mol Cell Biol 19:4582–4591

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Esnault C, Gualdrini F, Horswell S, Kelly G, Stewart A, East P, Matthews N, Treisman R (2017) ERK-induced activation of TCF family of SRF cofactors initiates a chromatin modification cascade associated with transcription. Mol Cell 65:1081–1095.e1085

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Janknecht R, Nordheim A (1992) Elk-1 protein domains required for direct and SRF-assisted DNA-binding. Nucleic Acids Res 20:3317–3324

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Janknecht R, Ernst WH, Pingoud V, Nordheim A (1993) Activation of ternary complex factor Elk-1 by MAP kinases. EMBO J 12:5097–5104

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Pilotto S, Speranzini V, Marabelli C, Rusconi F, Toffolo E, Grillo B, Battaglioli E, Mattevi A (2016) LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors. Hum Mol Genet 25(12):2578-2587

  31. Rusconi F, Mancinelli E, Colombo G, Cardani R, Da Riva L, Bongarzone I, Meola G, Zippel R (2010) Proteome profile in myotonic dystrophy type 2 myotubes reveals dysfunction in protein processing and mitochondrial pathways. Neurobiol Dis 38:273–280

    CAS  PubMed  Google Scholar 

  32. Rusconi F, Paganini L, Braida D, Ponzoni L, Toffolo E, Maroli A, Landsberger N, Bedogni F et al (2014) LSD1 neurospecific alternative splicing controls neuronal excitability in mouse models of epilepsy. Cereb Cortex 25(9):2729-40

    PubMed  Google Scholar 

  33. Bassani S, Cwetsch AW, Gerosa L, Serratto GM, Folci A, Hall IF, Mazzanti M, Cancedda L et al (2018) The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons. Hum Mol Genet 27:1027–1038

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Toffolo E, Rusconi F, Paganini L, Tortorici M, Pilotto S, Heise C, Verpelli C, Tedeschi G et al (2014) Phosphorylation of neuronal lysine-specific demethylase 1LSD1/KDM1A impairs transcriptional repression by regulating interaction with CoREST and histone deacetylases HDAC1/2. J Neurochem 128:603–616

    CAS  PubMed  Google Scholar 

  35. Zibetti C, Adamo A, Binda C, Forneris F, Toffolo E, Verpelli C, Ginelli E, Mattevi A et al (2010) Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. J Neurosci 30:2521–2532

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brewer GJ, Torricelli JR, Evege EK, Price PJ (1993) Optimized survival of hippocampal neurons in B27-supplemented neurobasal, a new serum-free medium combination. J Neurosci Res 35:567–576

    CAS  PubMed  Google Scholar 

  37. Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D (2002) Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295:868–872

    CAS  PubMed  Google Scholar 

  38. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM et al (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868

    CAS  PubMed  Google Scholar 

  39. Stritt C, Stern S, Harting K, Manke T, Sinske D, Schwarz H, Vingron M, Nordheim A et al (2009) Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression. Nat Neurosci 12:418–427

    CAS  PubMed  Google Scholar 

  40. Meyer zu Reckendorf C, Anastasiadou S, Bachhuber F, Franz-Wachtel M, Macek B, Knöll B (2016) Proteomic analysis of SRF associated transcription complexes identified TFII-I as modulator of SRF function in neurons. Eur J Cell Biol 95:42–56

    CAS  PubMed  Google Scholar 

  41. Davis FJ, Gupta M, Camoretti-Mercado B, Schwartz RJ, Gupta MP (2003) Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4. Implications in cardiac muscle gene regulation during hypertrophy. J Biol Chem 278:20047–20058

    CAS  PubMed  Google Scholar 

  42. Kuzniewska B, Nader K, Dabrowski M, Kaczmarek L, Kalita K (2016) Adult deletion of SRF increases epileptogenesis and decreases activity-induced gene expression. Mol Neurobiol 53:1478–1493

    CAS  PubMed  Google Scholar 

  43. Li CL, Sathyamurthy A, Oldenborg A, Tank D, Ramanan N (2014) SRF phosphorylation by glycogen synthase kinase-3 promotes axon growth in hippocampal neurons. J Neurosci 34:4027–4042

    PubMed  PubMed Central  Google Scholar 

  44. Wang J, Telese F, Tan Y, Li W, Jin C, He X, Basnet H, Ma Q et al (2015) LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat Neurosci 18:1256–1264

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Olson EN, Nordheim A (2010) Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 11:353–365

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Scandaglia M, Benito E, Morenilla-Palao C, Fiorenza A, Del Blanco B, Coca Y, Herrera E, Barco A (2015) Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly. Sci Rep 5:17470

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Del Blanco B, Guiretti D, Tomasoni R, Lopez-Cascales MT, Muñoz-Viana R, Lipinski M, Scandaglia M, Coca Y et al (2019) CBP and SRF co-regulate dendritic growth and synaptic maturation. Cell Death Differ. Mar 8

  48. Cahill ME, Walker DM, Gancarz AM, Wang ZJ, Lardner CK, Bagot RC, Neve RL, Dietz DM et al (2018) The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry 23:1474–1486

    CAS  PubMed  Google Scholar 

  49. Cahill ME, Walker DM, Gancarz AM, Wang ZJ, Lardner CK, Bagot RC, Neve RL (2017) Dietz DM. Nestler EJ, The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry

    Google Scholar 

  50. Kaneda M, Sakagami H, Hida Y, Ohtsuka T, Satou N, Ishibashi Y, Fukuchi M, Krysiak A et al (2018) Synaptic localisation of SRF coactivators, MKL1 and MKL2, and their role in dendritic spine morphology. Sci Rep 8:727

    PubMed  PubMed Central  Google Scholar 

  51. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S (2000) The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 20:4563–4572

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Richardson CL, Tate WP, Mason SE, Lawlor PA, Dragunow M, Abraham WC (1992) Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus. Brain Res 580:147–154

    CAS  PubMed  Google Scholar 

  53. Abraham WC, Dragunow M, Tate WP (1991) The role of immediate early genes in the stabilization of long-term potentiation. Mol Neurobiol 5:297–314

    CAS  PubMed  Google Scholar 

  54. Ovtscharoff W, Segal M, Goldin M, Helmeke C, Kreher U, Greenberger V, Herzog A, Michaelis B et al (2008) Electron microscopic 3D-reconstruction of dendritic spines in cultured hippocampal neurons undergoing synaptic plasticity. Dev Neurobiol 68:870–876

    PubMed  Google Scholar 

  55. Appleby VJ, Corrêa SA, Duckworth JK, Nash JE, Noël J, Fitzjohn SM, Collingridge GL, Molnár E (2011) LTP in hippocampal neurons is associated with a CaMKII-mediated increase in GluA1 surface expression. J Neurochem 116:530–543

    CAS  PubMed  Google Scholar 

  56. Molnár E (2011) Long-term potentiation in cultured hippocampal neurons. Semin Cell Dev Biol 22:506–513

    PubMed  Google Scholar 

  57. Hunter RG, McCarthy KJ, Milne TA, Pfaff DW, McEwen BS (2009) Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci U S A 106:20912–20917

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A et al (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404

    CAS  PubMed  Google Scholar 

  59. Knöll B, Kretz O, Fiedler C, Alberti S, Schütz G, Frotscher M, Nordheim A (2006) Serum response factor controls neuronal circuit assembly in the hippocampus. Nat Neurosci 9:195–204

    PubMed  Google Scholar 

  60. Parkitna JR, Bilbao A, Rieker C, Engblom D, Piechota M, Nordheim A, Spanagel R, Schütz G (2010) Loss of the serum response factor in the dopamine system leads to hyperactivity. FASEB J 24:2427–2435

    CAS  PubMed  Google Scholar 

  61. Janknecht R, Hipskind RA, Houthaeve T, Nordheim A, Stunnenberg HG (1992) Identification of multiple SRF N-terminal phosphorylation sites affecting DNA binding properties. EMBO J 11:1045–1054

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Li W, Xu X, Pozzo-Miller L (2016) Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors. Proc Natl Acad Sci U S A 113:E1575–E1584

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Xu X, Pozzo-Miller L (2017) EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice. J Physiol 595:5699–5712

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Musazzi L, Tornese P, Sala N, Popoli M (2017) Acute or chronic? A stressful question. Trends Neurosci 40:525–535

    CAS  PubMed  Google Scholar 

  65. Hyman S (2014) Mental health: depression needs large human-genetics studies. Nature 515:189–191

    CAS  PubMed  Google Scholar 

  66. DiLuca M, Olesen J (2014) The cost of brain diseases: a burden or a challenge? Neuron 82:1205–1208

    CAS  PubMed  Google Scholar 

  67. Vialou V, Feng J, Robison AJ, Nestler EJ (2013) Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 53:59–87

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Maria Passafaro, Alessandro Ieraci, Federica Giona, and Elena Romito for their supportive help along with stimulating discussions.

Funding

This study was financially supported by the funding agencies Ministero dell’Istruzione, dell’Università e della Ricerca (grant Epigenomics Flagship Project), Telethon Foundation project (grant no. GGP14074), and Fondazione Cariplo (grant no. 2016-0204) to E.B., and Fondazione Cariplo (grant no. 2014-0972) to F.R.

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Author notes

  1. Laura Gerosa, Barbara Grillo and Chiara Forastieri equally contributed to the work.

  2. The corresponding authors, Elena Battaglioli and Francesco Rusconi, equally contributed to the work.

Authors and Affiliations

  1. Institute of Neuroscience, Consiglio Nazionale delle Ricerche (CNR), Via Vanvitelli, 32, 20129, Milan, Italy

    Laura Gerosa, Silvia Bassani & Elena Battaglioli

  2. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale and Centro di Eccellenza per le Malattie Neurodegenerative (CEND), Laboratory of Neuroepigenetics, Università degli Studi di Milano, Via F.lli Cervi 93, 20090, Segrate, Italy

    Barbara Grillo, Chiara Forastieri, Alessandra Longaretti, Emanuela Toffolo, Elena Battaglioli & Francesco Rusconi

  3. Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Università degli Studi di Milano, Via Balzaretti, 9, 20129, Milan, Italy

    Alessandra Mallei & Maurizio Popoli

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  1. Laura Gerosa
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Contributions

LG, BG, CF, AL, ET, AM, and SB performed and interpreted the experiments. MP, EB, and FR conceived the work. EB and FR designed, interpreted the experiments and wrote the manuscript.

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Correspondence to Elena Battaglioli or Francesco Rusconi.

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Gerosa, L., Grillo, B., Forastieri, C. et al. SRF and SRFΔ5 Splicing Isoform Recruit Corepressor LSD1/KDM1A Modifying Structural Neuroplasticity and Environmental Stress Response. Mol Neurobiol 57, 393–407 (2020). https://doi.org/10.1007/s12035-019-01720-8

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