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Can Valproic Acid Regulate Neurogenesis from Nestin+ Cells in the Adult Midbrain?

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Abstract

Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) causes the motor symptoms (e.g. tremor, muscle rigidity, bradykinesia, postural instability) of Parkinson’s disease (PD). It is generally agreed that replacing these neurons will provide better motor symptom relief and fewer side effects than current pharmacotherapies. One potential approach to this is up-regulating endogenous DA neurogenesis in SNc. In the present study, we conducted bioinformatics analyses to identify signalling pathways that control expression of Pax6 and Msx1 genes, which have been identified as potentially important neurogenic regulators in the adult midbrain. From this Valproic acid (VPA) was identified as a regulator of these pathways, and we tested VPA for its ability to regulate midbrain neurogenesis in adult mice. VPA was infused directly into the midbrain of adult NesCreERT2/R26eYFP mice using osmotic pumps attached to implanted cannula. These mice enable permanent eYFP+ labelling of adult Nestin-expressing neural precursor cells and their progeny/ontogeny. VPA did not affect the number of eYFP+ midbrain cells, but significantly reduced the number of Pax6+, Pax6+/NeuN+, eYFP+/NeuN+ and eYFP−/NeuN+ cells. However, this reduction in NeuN expression was probably via VPA’s Histone de-acetylase inhibitory properties rather than reduced neuronal differentiation by eYFP + cells. We conclude that Pax6 and Msx1 are not viable targets for regulating neurogenesis in the adult midbrain.

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References

  1. Noyes K, Liu H, Li Y, Holloway R, Dick AW (2006) Economic burden associated with Parkinson’s disease on elderly medicare beneficiaries. Mov Disord 21:362–372

    Article  PubMed  Google Scholar 

  2. Braybrook M, O’Connor S, Churchward P, Perera T, Farzanehfar P, Horne M (2016) An Ambulatory Tremor Score for Parkinson’s disease. J Parkinson’s Dis 6:723–731

    Article  Google Scholar 

  3. Farzanehfar P (2016) Towards a better treatment option for Parkinson’s disease: a review of adult neurogenesis. Neurochem Res, 41:3161–3170

    Article  CAS  PubMed  Google Scholar 

  4. Farzanehfar P (2016) An anatomical and single-cell gene expression characterisation of putative neurogenesis from nestin-expressing cells in the adult mouse midbrain, Ph.D. thesis, The University of Melbourne.

  5. Shan X, Chi L, Bishop M, Luo C, Lien L, Zhang Z et al (2006) Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease-like mice. Stem Cells 24:1280–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Farzanehfar P, Lu SS, Dey A, Musiienko D, Baagil H, Horne MK et al (2017) Evidence of functional duplicity of Nestin expression in the adult mouse midbrain. Stem Cell Res 19:82–93

    Article  CAS  PubMed  Google Scholar 

  7. Imayoshi I, Ohtsuka T, Metzger D, Chambon P, Kageyama R (2006) Temporal regulation of Cre recombinase activity in neural stem cells. Genesis 44:233–238

    Article  CAS  PubMed  Google Scholar 

  8. Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM et al (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Downing T (2013) Biomaterials for cell engineering and regenerative medicine University of California, Berkeley

    Google Scholar 

  10. Chang C-Z, Wu S-C, Lin C-L, Kwan A-L (2015) Valproic acid attenuates intercellular adhesion molecule-1 and E-selectin through a chemokine ligand 5 dependent mechanism and subarachnoid hemorrhage induced vasospasm in a rat model. J Inflamm 12:27

    Article  Google Scholar 

  11. OsUmi N (2001) The role of paxo in brain patterning. Tohoku J Exp Med 193:163

    Article  CAS  PubMed  Google Scholar 

  12. Simpson TI, Simpson D (2002) Price, Pax6; a pleiotropic player in development. Bioessays 24:1041–1051

    Article  CAS  PubMed  Google Scholar 

  13. Osumi N, Osumi H, Shinohara K, Numayama Tsuruta M Maekawa M (2008)Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator. Stem Cells 26:1663–1672

    Article  CAS  PubMed  Google Scholar 

  14. Sakurai K, Osumi N (2008) The neurogenesis-controlling factor, Pax6, inhibits proliferation and promotes maturation in murine astrocytes. J Neurosci 28:4604–4612

    Article  CAS  PubMed  Google Scholar 

  15. Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B et al (2006) Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124:393–405

    Article  CAS  PubMed  Google Scholar 

  16. Ang S-L (2006) “Transcriptional control of midbrain dopaminergic neuron development”. Development 133:3499–3506

    Article  CAS  PubMed  Google Scholar 

  17. Mikkola I, Bruun JA, Holm T, Johansen T (2001) Superactivation of Pax6-mediated transactivation from paired domain-binding sites by dna-independent recruitment of different homeodomain proteins. J Biol Chem 276:4109–4118

    Article  CAS  PubMed  Google Scholar 

  18. Subramanian L, Sarkar A, Shetty A, Muralidharan B, Padmanabhan H, Piper M et al (2011) Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus. Proc Natl Acad Sci USA 108:E265–E274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hou P-S, Chuang C-Y, Kao C-F, Chou S-J, Stone L, Ho H-N et al (2013) LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1. Nucleic Acids Res 41:7753–7770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang L, Zhang P, Mathers M, Jamrich M (2000) Function ofRx, but notPax6, is essential for the formation of retinal progenitor cells in mice. Genesis 28:135–142

    Article  CAS  PubMed  Google Scholar 

  21. Sasai Y (1998) Identifying the missing links: genes that connect neural induction and primary neurogenesis in vertebrate embryos. Neuron 21:455–458

    Article  CAS  PubMed  Google Scholar 

  22. Bendall A, Bendall D, Rincon Limas J, Botas C, Abate S (1998) Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity. Differentiation 63:151–157

    Article  CAS  PubMed  Google Scholar 

  23. Visvader MJ (2003) LIM-domain-binding protein 1: a multifunctional cofactor that interacts with diverse proteins. EMBO Rep 4:1132–1137

    Article  PubMed  PubMed Central  Google Scholar 

  24. Dreyer SD, Morello R, German MS, Zabel B, Winterpacht A, Lunstrum GP et al (2000) LMX1B transactivation and expression in nail-patella syndrome. Hum Mol Genet 9:1067–1074

    Article  CAS  PubMed  Google Scholar 

  25. Jurata LW, Pfaff SL, Gill GN (1998) “The nuclear LIM domain interactor NLI mediates homo- and heterodimerization of LIM domain transcription factors. J Biol Chem 273:3152–3157

    Article  CAS  PubMed  Google Scholar 

  26. Ravasi T, Ravasi H, Suzuki C, Cannistraci S, Katayama V, Bajic K et al (2010) An atlas of combinatorial transcriptional regulation in mouse and man. Cell 140:744–752

    Article  CAS  PubMed  Google Scholar 

  27. Kempermann G, Chesler E, Lu L, Williams R, Gage F (2006) Natural variation and genetic covariance in adult hippocampal neurogenesis. Proc Natl Acad Sci USA 103:780–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Waldmann T, Waldmann E, Rempel N, Balmer A, König R, Kolde J et al (2014) Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol 27:408–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Krug A, Krug R, Kolde J, Gaspar E, Rempel N, Balmer K et al (2013) Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol 87:123–143

    Article  CAS  PubMed  Google Scholar 

  30. Balmer N, Balmer S, Klima E, Rempel V, Ivanova R, Kolde M et al (2014) From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol 88:1451–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Balmer N, Weng M, Zimmer B, Ivanova V, Chambers S, Nikolaeva E et al (2012) Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet 21:4104–4114

    Article  CAS  PubMed  Google Scholar 

  32. Laeng RL, Pitts AL, Lemire CE, Drabik A, Weiner H, Tang R et al (2004) The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem 91:238–251

    Article  CAS  PubMed  Google Scholar 

  33. Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P et al (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24:6590–6599

    Article  CAS  PubMed  Google Scholar 

  34. Yu J-Y, Park SH, J.-s. Kim, Lee Y-S (2009) and Son, Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation. Neuropharmacology 56:473–480

    Article  CAS  PubMed  Google Scholar 

  35. Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH (2004) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci USA 101:16659–16664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu XS, Chopp H, Kassis LF, Jia A, Hozeska-Solgot RL, Zhang C et al (2012) Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience 220:313–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Umka J, Mustafa S, ElBeltagy M, Thorpe A, Latif L, Bennett G et al (2010) Valproic acid reduces spatial working memory and cell proliferation in the hippocampus. Neuroscience 166:15–22

    Article  CAS  PubMed  Google Scholar 

  38. Jessberger S, Nakashima K, Clemenson GD, Mejia E, Mathews E, Ure K et al (2007) Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci 27:5967–5975

    Article  CAS  PubMed  Google Scholar 

  39. Monti B, Gatta V, Piretti F, Raffaelli SS, Virgili M, Contestabile A (2010) Valproic acid is neuroprotective in the rotenone rat model of Parkinson’s disease: involvement of α-synuclein. Neurotox Res 17:130–141

    Article  CAS  PubMed  Google Scholar 

  40. Kidd SK, Schneider JS (2011) Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience 194:189–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mahmoud F, Tampi RR (2011) Valproic acid-induced parkinsonism in the elderly: a comprehensive review of the literature. Am J Geriatr Pharmacother 9:405–412

    Article  CAS  PubMed  Google Scholar 

  42. Silver SA (2013) Factor valproic acid-induced parkinsonism: Levodopa responsiveness with dyskinesia. Parkinsonism Relat Disord 19:758–760

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant from the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Florey Institute for Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia

    Parisa Farzanehfar, Malcolm K. Horne & Tim D. Aumann

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  1. Parisa Farzanehfar
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  2. Malcolm K. Horne
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  3. Tim D. Aumann
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Correspondence to Parisa Farzanehfar.

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Farzanehfar, P., Horne, M.K. & Aumann, T.D. Can Valproic Acid Regulate Neurogenesis from Nestin+ Cells in the Adult Midbrain?. Neurochem Res 42, 2127–2134 (2017). https://doi.org/10.1007/s11064-017-2259-z

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  • DOI: https://doi.org/10.1007/s11064-017-2259-z

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