CoChat
Sign Up
Cited by 25Neuroscience and Neuropharmacology ResearchRNA Research and SplicingGenetics and Neurodevelopmental Disorders

Alterations in mossy fiber physiology and GAP‐43 expression and function in transgenic mice overexpressing HuD

Open access
Tanner, Daniel C., Qiu, Shenfeng, Bolognani, Federico, Partridge, L. Donald, Weeber, Edwin J., Perrone‐Bizzozero, Nora I·2008·Hippocampus
DOI 10.1002/hipo.20442PMC PMC2766808
Open this paper in CoChat — free account

Abstract

HuD is a neuronal RNA‐binding protein associated with the stabilization of mRNAs for GAP‐43 and other neuronal proteins that are important for nervous system development and learning and memory mechanisms. To better understand the function of this protein, we generated transgenic mice expressing human HuD (HuD‐Tg) in adult forebrain neurons. We have previously shown that expression of HuD in adult dentate granule cells results in an abnormal accumulation of GAP‐43 mRNA via posttranscriptional mechanisms. Here we show that this mRNA accumulation leads to the ectopic expression of GAP‐43 protein in mossy fibers. Electrophysiological analyses of the mossy fiber to CA3 synapse of HuD‐Tg mice revealed increases in paired‐pulse facilitation (PPF) at short interpulse intervals and no change in long‐term potentiation (LTP). Presynaptic calcium transients at the same synapses exhibited faster time constants of decay, suggesting a decrease in the endogenous Ca 2+ buffer capacity of mossy fiber terminals of HuD‐Tg mice. Under resting conditions, GAP‐43 binds very tightly to calmodulin sequestering it and then releasing it upon PKC‐dependent phosphorylation. Therefore, subsequent studies examined the extent of GAP‐43 phosphorylation and its association to calmodulin. We found that despite the increased GAP‐43 expression in HuD‐Tg mice, the levels of PKC‐phosphorylated GAP‐43 were decreased in these animals. Furthermore, in agreement with the increased proportion of nonphosphorylated GAP‐43, HuD‐Tg mice showed increased binding of calmodulin to this protein. These results suggest that a significant amount of calmodulin may be trapped in an inactive state, unable to bind free calcium, and activate downstream signaling pathways. In conclusion, we propose that an unregulated expression of HuD disrupts mossy fiber physiology in adult mice in part by altering the expression and phosphorylation of GAP‐43 and the amount of free calmodulin available at the synaptic terminal. © 2008 Wiley‐Liss, Inc.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/hipo.20442

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • HuD-Tg mice showed enhanced sprouting of GAP-43-containing mossy fibers to the CA3 region, ectopic expression of GAP-43 protein in the DG, and increased GAP-43 and calmodulin binding, possibly causing altered calcium signalling.

    “Detailed analysis of these mice showed enhanced sprouting of GAP-43-containing mossy fibers to the CA3 region, ectopic expression of GAP-43 protein in the DG, and increased GAP-43 and calmodulin binding, possibly causing altered calcium signalling (Tanner et al. 2008).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Tanner et al. 2008

    The Results report GAP-43-positive mossy fibers in CA3, increased GAP-43 staining in the dentate gyrus, and increased calmodulin binding to GAP-43; the Conclusions propose that calmodulin sequestration may alter calcium signaling (pages unavailable). But the Results do not establish enhanced mossy-fiber sprouting: the authors say the fibers interpreted as possible sprouts could instead have other origins. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 46

  1. Akers RF, Routtenberg A. Protein kinase C phosphorylates a 47 Mr protein (F1) directly related to synaptic plasticity. Brain Res. 1985;334(1):147–51. doi: 10.1016/0006-8993(85)90576-1. [DOI] [PubMed] [Google Scholar] · DOI
  2. Alexander KA, Cimler BM, Meier KE, Storm DR. Regulation of calmodulin binding to P-57. A neurospecific calmodulin binding protein. J Biol Chem. 1987;262(13):6108–13. [PubMed] [Google Scholar]
  3. Anderson KD, Morin MA, Beckel-Mitchener A, Mobarak CD, Neve RL, Furneaux HM, Burry R, Perrone-Bizzozero NI. Overexpression of HuD, but not of its truncated form HuD I+II, promotes GAP-43 gene expression and neurite outgrowth in PC12 cells in the absence of nerve growth factor. J Neurochem. 2000;75(3):1103–14. doi: 10.1046/j.1471-4159.2000.0751103.x. [DOI] [PubMed] [Google Scholar] · DOI
  4. Anderson KD, Sengupta J, Morin M, Neve RL, Valenzuela CF, Perrone-Bizzozero NI. Overexpression of HuD accelerates neurite outgrowth and increases GAP-43 mRNA expression in cortical neurons and retinoic acid-induced embryonic stem cells in vitro. Exp Neurol. 2001;168(2):250–8. doi: 10.1006/exnr.2000.7599. [DOI] [PubMed] [Google Scholar] · DOI
  5. Atluri PP, Regehr WG. Determinants of the time course of facilitation at the granule cell to Purkinje cell synapse. J Neurosci. 1996;16(18):5661–71. doi: 10.1523/JNEUROSCI.16-18-05661.1996. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  6. Bakheet T, Williams BR, Khabar KS. ARED 3.0: the large and diverse AU-rich transcriptome. Nucleic Acids Res. 2006;34(Database issue):D111–4. doi: 10.1093/nar/gkj052. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  7. Barami K, Iversen K, Furneaux H, Goldman SA. Hu protein as an early marker of neuronal phenotypic differentiation by subependymal zone cells of the adult songbird forebrain. J Neurobiol. 1995;28(1):82–101. doi: 10.1002/neu.480280108. [DOI] [PubMed] [Google Scholar] · DOI
  8. Bendotti C, Baldessari S, Pende M, Southgate T, Guglielmetti F, Samanin R. Relationship between GAP-43 expression in the dentate gyrus and synaptic reorganization of hippocampal mossy fibres in rats treated with kainic acid. Eur J Neurosci. 1997;9(1):93–101. doi: 10.1111/j.1460-9568.1997.tb01357.x. [DOI] [PubMed] [Google Scholar] · DOI
  9. Benowitz LI, Apostolides PJ, Perrone-Bizzozero N, Finklestein SP, Zwiers H. Anatomical distribution of the growth-associated protein GAP-43/B-50 in the adult rat brain. J Neurosci. 1988;8(1):339–52. doi: 10.1523/JNEUROSCI.08-01-00339.1988. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. Benowitz LI, Routtenberg A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 1997;20(2):84–91. doi: 10.1016/s0166-2236(96)10072-2. [DOI] [PubMed] [Google Scholar] · DOI
  11. Berggard T, Miron S, Onnerfjord P, Thulin E, Akerfeldt KS, Enghild JJ, Akke M, Linse S. Calbindin D28k exhibits properties characteristic of a Ca2+ sensor. J Biol Chem. 2002;277(19):16662–72. doi: 10.1074/jbc.M200415200. [DOI] [PubMed] [Google Scholar] · DOI
  12. Blatow M, Caputi A, Burnashev N, Monyer H, Rozov A. Ca2+ buffer saturation underlies paired pulse facilitation in calbindin-D28k-containing terminals. Neuron. 2003;38(1):79–88. doi: 10.1016/s0896-6273(03)00196-x. [DOI] [PubMed] [Google Scholar] · DOI
  13. Bolognani F, Merhege M, Twiss A, Nora J, Perrone-Bizzozero I. Dendritic localization of the RNA-binding protein HuD in hippocampal neurons: association with polysomes and upregulation during contextual learning. Neurosci Letters. 2004;371:152–157. doi: 10.1016/j.neulet.2004.08.074. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  14. Bolognani F, Qiu S, Tanner DC, Paik J, Perrone-Bizzozero NI, Weeber EJ. Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD. Neurobiol Learn Mem. 2007a;87(4):635–43. doi: 10.1016/j.nlm.2006.11.004. [DOI] [PubMed] [Google Scholar] · DOI
  15. Bolognani F, Tanner DC, Merhege M, Deschenes-Furry J, Jasmin B, Perrone-Bizzozero NI. In vivo post-transcriptional regulation of GAP-43 mRNA by overexpression of the RNA-binding protein HuD. J Neurochem. 2006;96(3):790–801. doi: 10.1111/j.1471-4159.2005.03607.x. [DOI] [PubMed] [Google Scholar] · DOI
  16. Bolognani F, Tanner DC, Nixon S, Okano HJ, Okano H, Perrone-Bizzozero NI. Coordinated Expression of HuD and GAP-43 in Hippocampal Dentate Granule Cells During Developmental and Adult Plasticity. Neurochem Res. 2007b Jun 19; doi: 10.1007/s11064-007-9388-8. [Epub ahead of print] [DOI] [PubMed] [Google Scholar] · DOI
  17. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  18. Cantallops I, Routtenberg A. Activity-dependent regulation of axonal growth: posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus. J Neurobiol. 1999;41(2):208–20. [PubMed] [Google Scholar]
  19. Clayton GH, Perez GM, Smith RL, Owens GC. Expression of mRNA for the elav-like neural-specific RNA binding protein, HuD, during nervous system development Brain Res. Dev Brain Res. 1998;109:271–280. doi: 10.1016/s0165-3806(98)00074-1. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  20. Dekker LV, De Graan PN, Oestreicher AB, Versteeg DH, Gispen WH. Inhibition of noradrenaline release by antibodies to B-50 (GAP-43) Nature. 1989;342(6245):74–6. doi: 10.1038/342074a0. [DOI] [PubMed] [Google Scholar] · DOI
  21. Haruta T, Takami N, Ohmura M, Misumi Y, Ikehara Y. Ca2+-dependent interaction of the growth-associated protein GAP-43 with the synaptic core complex. Biochem J. 1997;325 (Pt 2):455–63. doi: 10.1042/bj3250455. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. Holahan MR, Honegger KS, Tabatadze N, Routtenberg A. GAP-43 gene expression regulates information storage. Learn Mem. 2007;14(6):407–15. doi: 10.1101/lm.581907. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  23. Hulo S, Alberi S, Laux T, Muller D, Caroni P. A point mutant of GAP-43 induces enhanced short-term and long-term hippocampal plasticity. Eur J Neurosci. 2002;15(12):1976–82. doi: 10.1046/j.1460-9568.2002.02026.x. [DOI] [PubMed] [Google Scholar] · DOI
  24. Ivins KJ, Neve KA, Feller DJ, Fidel SA, Neve RL. Antisense GAP-43 inhibits the evoked release of dopamine from PC12 cells. J Neurochem. 1993;60(2):626–33. doi: 10.1111/j.1471-4159.1993.tb03194.x. [DOI] [PubMed] [Google Scholar] · DOI
  25. Kohn DT, Tsai KC, Cansino VV, Neve RL, Perrone-Bizzozero NI. Role of highly conserved pyrimidine-rich sequences in the 3′ untranslated region of the GAP-43 mRNA in mRNA stability and RNA-protein interactions. Brain Res Mol Brain Res. 1996;36(2):240–50. doi: 10.1016/0169-328x(95)00239-o. [DOI] [PubMed] [Google Scholar] · DOI
  26. Liu YC, Storm DR. Regulation of free calmodulin levels by neuromodulin: neuron growth and regeneration. Trends Pharmacol Sci. 1990;11(3):107–11. doi: 10.1016/0165-6147(90)90195-e. [DOI] [PubMed] [Google Scholar] · DOI
  27. Lovinger DM, Colley PA, Akers RF, Nelson RB, Routtenberg A. Direct relation of long-term synaptic potentiation to phosphorylation of membrane protein F1, a substrate for membrane protein kinase C. Brain Res. 1986;399(2):205–11. doi: 10.1016/0006-8993(86)91510-6. [DOI] [PubMed] [Google Scholar] · DOI
  28. Meberg PJ, Routtenberg A. Selective expression of protein F1/(GAP-43) mRNA in pyramidal but not granule cells of the hippocampus. Neuroscience. 1991;45(3):721–33. doi: 10.1016/0306-4522(91)90284-u. [DOI] [PubMed] [Google Scholar] · DOI
  29. Mobarak CD, Anderson KD, Morin M, Beckel-Mitchener A, Rogers SL, Furneaux H, King P, Perrone-Bizzozero NI. The RNA-binding protein HuD is required for GAP-43 mRNA stability, GAP-43 gene expression, and PKC-dependent neurite outgrowth in PC12 cells. Mol Biol Cell. 2000;11(9):3191–203. doi: 10.1091/mbc.11.9.3191. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  30. Namgung U, Routtenberg A. Transcriptional and post-transcriptional regulation of a brain growth protein: regional differentiation and regeneration induction of GAP-43. Eur J Neurosci. 2000;12(9):3124–36. doi: 10.1046/j.1460-9568.2000.00196.x. [DOI] [PubMed] [Google Scholar] · DOI
  31. Neve RL, Coopersmith R, McPhie DL, Santeufemio C, Pratt KG, Murphy CJ, Lynn SD. The neuronal growth-associated protein GAP-43 interacts with rabaptin-5 and participates in endocytosis. J Neurosci. 1998;18(19):7757–67. doi: 10.1523/JNEUROSCI.18-19-07757.1998. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. Nicoll RA, Schmitz D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci. 2005;6(11):863–76. doi: 10.1038/nrn1786. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  33. Okano HJ, Darnell RB. A hierarchy of Hu RNA binding proteins in developing and adult neurons. J Neurosci. 1997;17(9):3024–37. doi: 10.1523/JNEUROSCI.17-09-03024.1997. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  34. Pascale A, Gusev PA, Amadio M, Dottorini T, Govoni S, Alkon DL, Quattrone A. Increase of the RNA-binding protein HuD and posttranscriptional up-regulation of the GAP-43 gene during spatial memory. Proc Natl Acad Sci U S A. 2004;101(5):1217–22. doi: 10.1073/pnas.0307674100. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  35. Perrone-Bizzozero NI, Tanner D. GAP-43 in neural development and plasticity. In: Lajitha A, Lim R, editors. The handbook of neurochemistry and molecular neurobiology. 3. Heidelberg, Germany: Springer; 2006. pp. 315–329. [Google Scholar]
  36. Quattrone A, Pascale A, Nogues X, Zhao W, Gusev P, Pacini A, Alkon DL. Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins. Proc Natl Acad Sci U S A. 2001;98(20):11668–73. doi: 10.1073/pnas.191388398. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  37. Ramakers GM, De Graan PN, Urban IJ, Kraay D, Tang T, Pasinelli P, Oestreicher AB, Gispen WH. Temporal differences in the phosphorylation state of pre- and postsynaptic protein kinase C substrates B-50/GAP-43 and neurogranin during long-term potentiation. J Biol Chem. 1995;270(23):13892–8. doi: 10.1074/jbc.270.23.13892. [DOI] [PubMed] [Google Scholar] · DOI
  38. Routtenberg A, Cantallops I, Zaffuto S, Serrano P, Namgung U. Enhanced learning after genetic overexpression of a brain growth protein. Proc Natl Acad Sci U S A. 2000;97(13):7657–62. doi: 10.1073/pnas.97.13.7657. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  39. Schiess AR, Scullin CS, Partridge LD. Neurosteroid-induced enhancement of short-term facilitation involves a component downstream from presynaptic calcium in hippocampal slices. J Physiol. 2006;576(Pt 3):833–47. doi: 10.1113/jphysiol.2006.118505. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  40. Scott R, Rusakov DA. Main determinants of presynaptic Ca2+ dynamics at individual mossy fiber-CA3 pyramidal cell synapses. J Neurosci. 2006;26(26):7071–81. doi: 10.1523/JNEUROSCI.0946-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  41. Skene JH. GAP-43 as a ‘calmodulin sponge’ and some implications for calcium signalling in axon terminals. Neurosci Res Suppl. 1990;13:S112–25. doi: 10.1016/0921-8696(90)90040-a. [DOI] [PubMed] [Google Scholar] · DOI
  42. Smith CL, Afroz R, Bassell GJ, Furneaux HM, Perrone-Bizzozero NI, Burry RW. GAP-43 mRNA in growth cones is associated with HuD and ribosomes. J Neurobiol. 2004;61(2):222–35. doi: 10.1002/neu.20038. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  43. Sossin WS, DesGroseillers L. Intracellular trafficking of RNA in neurons. Traffic. 2006;7(12):1581–9. doi: 10.1111/j.1600-0854.2006.00500.x. [DOI] [PubMed] [Google Scholar] · DOI
  44. Urban NN, Henze DA, Barrionuevo G. Revisiting the role of the hippocampal mossy fiber synapse. Hippocampus. 2001;11(4):408–17. doi: 10.1002/hipo.1055. [DOI] [PubMed] [Google Scholar] · DOI
  45. Wang W, van Niekerk E, Willis DE, Twiss JL. RNA transport and localized protein synthesis in neurological disorders and neural repair. Dev Neurobiol. 2007;67(9):1166–82. doi: 10.1002/dneu.20511. [DOI] [PubMed] [Google Scholar] · DOI
  46. Zucker RS, Regehr WG. Short-term synaptic plasticity. Annu Rev Physiol. 2002;64:355–405. doi: 10.1146/annurev.physiol.64.092501.114547. [DOI] [PubMed] [Google Scholar] · DOI · Paper page

Cited by

Sorted by citations

Authors
Tanner, D. C., Qiu, S., Bolognani, F., Partridge, L. D., Weeber, E. J., & Perrone‐Bizzozero, N. I.
Affiliations
  • University of New Mexico (US)
  • Vanderbilt University (US)
Corresponding author
Perrone‐Bizzozero, Nora I
ORCID
Venue
Hippocampus
Publisher
Wiley
Published
2008-05-20
Volume
18
Issue
8
Pages
814-823
ISSN
  • 1050-9631 (ISSN-L)
  • 1098-1063
DOI
10.1002/hipo.20442
PMC
PMC2766808
OpenAlex
W2036711290
Cited by
25
References
2
Citations by year
2021: 2 · 2020: 1 · 2018: 2 · 2017: 3 · 2015: 2 · 2014: 1 · 2013: 2 · 2012: 4
FWCI
1.15
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Hippocampus (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (T32 AA1427)
  • National Institute on Aging (R01AG022574, AG 022574)
  • National Institute of Neurological Disorders and Stroke (NS 30255, R01NS030255)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
HUD, GAP-43, mossy fibers, calmodulin, paired-pulse facilitation, long-term potentiation, PKC phosphorylation, mRNA stabilization, dentate gyrus, transgenic mice, RNA-binding proteins, synaptic plasticity
MeSH terms
ELAV-Like Protein 4, Animals, Calcium, Calmodulin, Electrophysiology, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Protein Binding, Recombinant Proteins, RNA, Messenger, Gene Expression, Presynaptic Terminals, Mossy Fibers, Hippocampal, GAP-43 Protein, RNA Stability, Mice, ELAV Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review