Comparative Genomics of the BDNF Gene, Non-Canonical Modes of Transcriptional Regulation, and Neurological Disease

Abstract

Alternative splicing of genes in the central nervous system is ubiquitous and utilizes many different mechanisms. Splicing generates unique transcript or protein isoforms of the primary gene that result in shortened, lengthened, or reorganized products that may have distinct functions from the parent gene. Learning and memory genes respond selectively to a variety of environmental stimuli and have evolved a number of complex mechanisms for transcriptional regulation to act rapidly and flexibly to environmental demands. Their patterns of expression, however, are incompletely understood. Many activity-inducible genes generate transcripts by alternative splicing that have an unknown physiological or behavioral function. One such gene codes for the protein brain-derived neurotrophic factor (BDNF). BDNF is a neurotrophin whose expression is essential for cellular growth, synaptogenesis, and synaptic plasticity. It is an important model gene because of its complex structure and the variety of transcriptional mechanisms it displays for expression in response to external stimuli. Some of these are unexpected, or non-canonical, transcriptional control mechanisms that require further exploration in an activity-dependent context. In this review, a comparative genomics approach is taken to highlight the different forms of BDNF gene transcription including potential autoregulatory mechanisms. Modes of BDNF control have general implications for understanding the origins of several neurological disorders that are associated with reduced BDNF function.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3

Data Availability

NA

Code Availability

NA

References

  1. 1.

    Mery F (2013) Natural variation in learning and memory. Curr Opin Neurobiol 23:52–56

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Krause MA (2015) Evolutionary perspectives on learning: conceptual and methodological issues in the study of adaptive specializations. Anim Cogn 18:807–820

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Lyons MR, West AE (2011) Mechanisms of specificity in neuronal activity-regulated gene transcription. Prog Neurobiol 94:259–295

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. 4.

    Yap E-L, Greenberg ME (2018) Activity-regulated transcription: bridging the gap between neural activity and behavior. Neuron 100:330–348

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    Qureshi IA, Mehler MF (2012) Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci 13:528–541

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Flavell SW, Kim T-K, Gray JM, Harmin DA, Hemburg M, Hong EJ, Markenscoff-Papadimitriou E, Bear DM et al (2008) Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60:1022–1038

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Hermey G, Bluthgen N, Kuhl D (2017) Neuronal activity-regulated alternative mRNA splicing. Int J Biochem Cell Biol 91:184–193

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Cheng Z, Otto GM, Powers EN, Keskin A, Mertins P, Carr SA, Jovanovic M, Brar GA (2018) Pervasive, coordinated protein-level changes driven by transcript isoform switching during meiosis. Cell 172:910–923

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Karpova NN (2014) Role of BDNF epigenetics in activity-dependent neuronal plasticity. Neuropharmacology 76:709–718

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    West AE, Pruunsild P, Timmusk T (2014) Neurotrophins: transcription and translation. Handb Exp Pharmacol 220:67–100

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Modarresi F, Faghihi MA, Lopez-Toledano A, Fatemi RP, Magistri M, Brothers SP, van der Brug MP, Wahlestedt C (2012) Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 30:453–459

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Lipovich L, Dachet F, Cai J, Bagla S, Balan K, Jia H, Loeb JA (2012) Activity-dependent human brain coding/noncoding gene regulatory networks. Genetics 192:1133–1148

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Zheng Z, Keifer J (2020) Learning-dependent transcriptional regulation of BDNF by its truncated protein isoform in turtle. J Mol Neurosci. https://doi.org/10.1007/s12031-020-01722-5

  14. 14.

    Michalski B, Fahnestock M (2003) Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Res Mol Brain Res 111:148–154

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93:1412–1421

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S (2008) New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 59:201–220

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10:209–219

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Li W, Pozzo-Miller L (2014) BDNF deregulation in Rett syndrome. Neuropharmacology 76:737–746

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Keifer J, Zheng Z, Ambigapathy G (2015) A microRNA-BDNF negative feedback signaling loop in brain: implications for Alzheimer’s disease. Microrna 4:101–108

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Soto EJL, Gandal MJ, Gonatopoulos-Pournatzis T, Heller EA, Luo D, Zheng S (2019) Mechanisms of neuronal alternative splicing and strategies for therapeutic interventions. J Neurosci 39:8193–8199

    Article  Google Scholar 

  21. 21.

    Ule J, Blencowe BJ (2019) Alternative splicing regulatory networks: functions, mechanisms, and evolution. Mol Cell 76:329–345

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90:397–406

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85:525–535

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Yu Y, Zhang H, Byerly MS, Bacon LD, Porter TE, Liu GE, Song J (2009) Alternative splicing variants and DNA methylation status of BDNF in inbred chicken lines. Brain Res 1269:1–10

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Ambigapathy G, Zheng Z, Keifer J (2013) Identification of a functionally distinct truncated BDNF mRNA splice variant and protein in Trachemys scripta elegans. PLoS One 8:e67141

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Kidane AH, Heinrich G, RPH D, de Ruyck BA, Lubsen NH, Roubos EW, Jenks BG (2009) Differential neuroendocrine expression of multiple brain-derived neurotrophic factor transcripts. Endocrinology 150:1361–1368

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  27. 27.

    Tognoli C, Rossi F, di Cola F, Baj G, Tongiorgi E, Terova G, Saroglia M, Bernardini G et al (2010) Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in Dicentrarchus labrax. BMC Neurosci 11:4

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Heinrich G (2003) A novel BDNF gene promoter directs expression to skeletal muscle. BMC Neurosci 4:11

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Liu Q-R, Walther D, Drgon T, Polesskaya O, Lesnick TG, Strain KJ, de Andrade M, Bower JH et al (2005) Human brain derived neurotrophic factor (BDNF) genes, splicing pattern, and assessments of associations with substance abuse and Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet 134B:93–103

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic regulation of bdnf gene transcription in the consolidation of fear memory. J Neurosci 28:10576–10586

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Mizuno K, Dempster E, Mill J, Giese KP (2012) Long-lasting regulation of hippocampal Bdnf gene transcription after contextual fear conditioning. Genes Brain Behav 11:651–659

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Bambah-Mukku D, Travaglia A, Chen DY, Pollonini G, Alberini CM (2014) A positive autoregulatory feedback loop via C/EBPβ mediates hippocampal memory consolidation. J Neurosci 34:12547–12559

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Ambigapathy G, Zheng Z, Keifer J (2015) Regulation of BDNF chromatin status and promoter accessibility in a neural correlate of associative learning. Epigenetics 10:981–993

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Park H, Poo M-M (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14:7–23

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  35. 35.

    Chiaruttini C, Sonego M, Baj G, Simonato M, Tongiorgi E (2008) BDNF mRNA splice variants display activity-dependent targeting to distinct hippocampal laminae. Mol Cell Neurosci 37:11–19

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  36. 36.

    Baj G, Leone E, Chao MV, Tongiorgi E (2011) Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments. Proc Natl Acad Sci U S A 108:16813–16818

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Maynard KR, Hobbs JW, Sukumar M, Kardian AS, Jimenez DV, Schloesser RJ, Martinowich K (2017) Bdnf mRNA variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus. Brain Struct Funct 222:3295–3307

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Gotz R, Raulf F, Schartl M (1992) Brain-derived neurotrophic factor is more highly conserved in structure and function than nerve growth factor during vertebrate evolution. J Neurochem 59:432–442

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  39. 39.

    Tettamanti G, Cattaneo AG, Gornati R, de Eguileor M, Bernardini G, Binelli G (2010) Phylogenesis of brain-derived neurotrophic factor (BDNF) in vertebrates. Gene 450:85–93

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  40. 40.

    Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9:2459–2464

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Jones KR, Reichardt LF (1990) Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci U S A 87:8060–8064

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Maisonpierre PC, Le Beau MM, Espinosa R, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME et al (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10:558–568

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Maisonpierre PC, Belluscio L, Conover JC, Yancopoulos GD (1992) Gene sequences of chicken BDNF and NT-3. DNA Seq 3:49–54

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Hashimoto M, Heinrich G (1997) Brain-derived neurotrophic factor gene expression in the developing zebrafish. Int J Dev Neurosci 15:983–997

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    D’Angelo L, de Girolamo P, Lucini C, Terzibasi ET, Baumgart M, Castaldo L, Cellerino A (2014) Brain-derived neurotrophic factor: mRNA expression and protein distribution in the brain of the teleost Nothobranchius furzeri. J Comp Neurol 522:1004–1030

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH et al (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487–491

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  48. 48.

    Keifer J, Sabirzhanov BE, Zheng Z, Li W, Clark TG (2009) Cleavage of proBDNF to BDNF by a tolloid-like metalloproteinase is required for acquisition of in vitro eyeblink classical conditioning. J Neurosci 29:14956–14964

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Yang J, Siao C-J, Nagappan G, Marinic T, Jing D, McGrath K, Chen Z-Y, Mark W et al (2009) Neuronal release of proBDNF. Nat Neurosci 12:113–115

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276:12660–12666

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  51. 51.

    Fayard B, Loeffler S, Weis J, Vogelin E, Kruttgen A (2005) The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR not to TrkA or TrkC. J Neurosci Res 80:18–28

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  52. 52.

    Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6:603–614

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  53. 53.

    Uegaki K, Kumanogoh H, Mizui T, Hirokawa T, Ishikawa Y, Kojima M (2017) BDNF binds its pro-peptide with high affinity and the common Val66Met polymorphism attenuates the interaction. Int J Mol Sci 18:1042

    PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    An JJ, Gharami K, Liao G-Y, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR et al (2008) Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134:175–187

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Lau AG, Irier HA, Gu J, Tian D, Ku L, Liu G, Xia M, Fritsch B et al (2010) Distinct 3′ UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF). Proc Natl Acad Sci U S A 107:15945–15950

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Li W, Zheng Z, Keifer J (2011) Transsynaptic EphB/ephrin-B signaling regulates growth of presynaptic boutons required for classical conditioning. J Neurosci 31:8441–8449

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Liu Q-R, Lu L, Zhu X-G, Gong J-P, Shaham Y, Uhl GR (2006) Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res 1067:1–12

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M, Persson H (1993) Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10:475–489

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Metsis M, Timmusk T, Arenas E, Persson H (1993) Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci U S A 90:8802–8806

  60. 60.

    Garzon D, Yu G, Fahnestock M (2002) A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. J Neurochem 82:1058–1064

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Zheng Z, Ambigapathy G, Keifer J (2017) MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in turtle. Elife 6:e25384

  62. 62.

    Koppel I, Tuvikene J, Lekk I, Timmusk T (2015) Efficient use of a translation start codon in BDNF exon I. J Neurochem 134:1015–1025

  63. 63.

    Keifer J, Armstrong KE, Houk JC (1995) In vitro classical conditioning of abducens nerve discharge in turtles. J Neurosci 15:5036–5048

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Zheng Z, Sabirzhanov B, Keifer J (2012) Two-stage AMPA receptor trafficking in classical conditioning and selective role for glutamate receptor subunit 4 (tGluA4) flop splice variant. J Neurophysiol 108:101–111

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Sala C, Futai K, Yamamoto K, Worley PF, Hayashi Y, Sheng M (2003) Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a. J Neurosci 23:6327–6337

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Manavella PA, Roqueiro G, Darling DS, Cabanillas AM (2007) The ZFHX1A gene is differentially autoregulated by its isoform. Biochem Biophys Res Commun 360:621–626

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67.

    Martinez M, Hinojosa M, Trombly D, Morin V, Stein J, Stein G, Javed A, Gutierrez SE (2016) Transcriptional auto-regulation of RUNX1 P1 promoter. PLoS One 11:e0149119

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Chen J, Tresenrider A, Chia M, DT MS, Spedale G, Jorgensen V, Liao H, van Werven FJ et al (2017) Kinetochore inactivation by expression of a repressive mRNA. Elife 6:e27417

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Chia M, Tresenrider A, Chen J, Spedale G, Jorgensen V, Unal E, van Werven FJ (2017) Transcription of a 5′ extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter. Elife 6:e27420

    PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Konieczny P, Stepniak-Konieczna E, Taylor K, Sznajder LJ, Sobczak K (2017) Autoregulation of MBNL1 function by exon 1 exclusion from MBNL1 transcript. Nucleic Acids Res 45:1760–1775

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  71. 71.

    Maicas M, Vazquez I, Alis R, Marcotegui N, Urquiza L, Cortes-Lavaud X, Cristobal I, Garcia-Sanchez MA et al (2017) The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells. Biochim Biophys Acta Gene Regul Mech 1860:721–729

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  72. 72.

    Williamson L, Saponaro M, Boeing S, East P, Mitter R, Kantidakis T, Kelly GP, Lobley A et al (2017) UV irradiation induces a non-coding RNA that functionally opposes the protein encoded by the same gene. Cell 168:843–855

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Bottai D, Guzowski JF, Schwartz MK, Kang SH, Xiao B, Lanahan A, Worley PF, Seeburg PH (2002) Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression. J Neurosci 22:167–175

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Niibori Y, Hayashi F, Hirai K, Matsui M, Inokuchi K (2007) Alternative poly(A) site-selection regulates the production of alternatively spliced vesl-1/homer1 isoforms that encode postsynaptic scaffolding proteins. Neurosci Res 57:399–410

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  75. 75.

    Magistri M, Faghihi MA, St. Laurent G III, Wahlestedt C (2012) Regulation of chromatin structure by long noncoding RNAs: Focus on natural antisense transcripts. Trends Genet 28:389–396

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Li W, Keifer J (2008) Coordinate action of pre- and postsynaptic brain-derived neurotrophic factor is required for AMPAR trafficking and acquisition of in vitro classical conditioning. Neuroscience 155:686–697

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Riva P, Ratti A, Venturin M (2016) The long non-coding RNAs in neurodegenerative diseases: novel mechanisms of pathogenesis. Curr Alzheimer Res 13:1219–1231

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  78. 78.

    Guo CC, Jiao CH, Gao ZM (2018) Silencing of lncRNA BDNF-AS attenuates Aβ25-35-induced neurotoxicity in PC12 cells by suppressing cell apoptosis and oxidative stress. Neurol Res 40:795–804

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  79. 79.

    Lu B, Nagappan G, Guan X, Nathan PJ, Wren P (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14:401–416

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  80. 80.

    Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A et al (2018) Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361:eaan8821

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. 81.

    de Pins B, Cifuentes-Diaz C, Farah AT, Lopez-Molina L, Montalban E, Sanch-Balsells A, Lopez A, Gines S et al (2019) Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties in the 5xFAD mouse model of Alzheimer disease. J Neurosci 39:2441–2458

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Sakai N, Tolbert LM, Duman RS (1999) Identification and functional analysis of novel cAMP response element binding protein splice variants lacking the basic/leucine zipper domain. Mol Pharmacol 56:917–925

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Michelhaugh SK, Vaitkevicius H, Wang J, Bouhamdan M, Krieg AR, Walker JL, Mendiratta V, Bannon MJ (2005) Dopamine neurons express multiple isoforms of the nuclear receptor nurr1 with diminished transcriptional activity. J Neurochem 95:1342–1350

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Lopez AJ, Hemstedt TJ, Jia Y, Hwang PH, Campbell RR, Kwapis JL, White AO, Chitnis O et al (2019) Epigenetic regulation of immediate-early gene Nr4a2/Nurr1 in the medial habenula during reinstatement of cocaine-associated behavior. Neuropharmacology 153:13–19

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Sassone-Corsi P, Sisson JC, Verma IM (1988) Transcriptional autoregulation of the proto-oncogene fos. Nature 334:314–319

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Cao X, Mahendran R, Guy GR, Tan YH (1993) Detection and characterization of cellular EGR-1 binding to its recognition site. J Biol Chem 268:16949–16957

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Keifer J, Summers CH (2016) Putting the “biology” back into “neurobiology”: the strength of diversity in animal model systems for neuroscience research. Front Syst Neurosci 10:69

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

I thank Cliff H. Summers for his valuable comments on the manuscript.

Funding

This study is supported by the Neuroscience Medical Research Fund (USD), and internal departmental funds were given to JK.

Author information

Affiliations

Authors

Contributions

JK conceptualized and wrote the paper.

Corresponding author

Correspondence to Joyce Keifer.

Ethics declarations

Ethics Approval

NA

Consent to Participate

NA

Consent for Publication

NA

Conflict of Interest

The author declares no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Keifer, J. Comparative Genomics of the BDNF Gene, Non-Canonical Modes of Transcriptional Regulation, and Neurological Disease. Mol Neurobiol (2021). https://doi.org/10.1007/s12035-021-02306-z

Download citation

Keywords

  • Alternative splicing
  • Comparative genomics
  • Activity-inducible genes
  • BDNF
  • Dominant negative