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Dev Neurosci 2010;32:184–196

Brain-Derived Neurotrophic Factor Attracts Geniculate Ganglion Neurites during Embryonic Targeting

Hoshino N. · Vatterott P. · Egwiekhor A. · Rochlin M.W.
Biology Department, Loyola University Chicago, Chicago, Ill., USA
email Corresponding Author

 goto top of outline Key Words

  • Axon
  • Guidance
  • Neurotrophin
  • Epithelium
  • Taste
  • Development

 goto top of outline Abstract

Geniculate axons are initially guided to discrete epithelial placodes in the lingual and palatal epithelium that subsequently differentiate into taste buds. In vivo approaches show that brain-derived neurotrophic factor (BDNF) mRNA is concentrated in these placodes, that BDNF is necessary for targeting taste afferents to these placodes, and that BDNF misexpression disrupts guidance. We used an in vitro approach to determine whether BDNF may act directly on geniculate axons as a trophic factor and as an attractant, and whether there is a critical period for responsiveness to BDNF. We show that BDNF promotes neurite outgrowth from geniculate ganglion explants dissected from embryonic day (E) 15, E18, infant, and adult rats cultured in collagen gels, and that there is a concentration optimum for neurite extension. Gradients of BDNF derived from slow-release beads caused the greatest bias in neurite outgrowth at E15, when axons approach the immature gustatory papillae. Further, neurites advanced faster toward the BDNF bead than away from it, even if the average amount of neurotrophic factor encountered was the same. We also found that neurites that contact BDNF beads did not advance beyond them. At E18, when axons would be penetrating pregustatory epithelium in vivo, BDNF continued to exert a tropic effect on geniculate neurites. However, at postnatal and adult stages, the influence of BDNF was predominantly trophic. Our data support a role for BDNF acting as an attractant for geniculate axons during a critical period that encompasses initial targeting but not at later stages.

Copyright © 2010 S. Karger AG, Basel

 goto top of outline References
  1. Mbiene JP: Taste placodes are primary targets of geniculate but not trigeminal sensory axons in mouse developing tongue. J Neurocytol 2004;33:617–629.
  2. Mbiene JP, Mistretta CM: Initial innervation of embryonic rat tongue and developing taste papillae: nerves follow distinctive and spatially restricted pathways. Acta Anat (Basel) 1997;160:139–158.
  3. Farbman AI, Mbiene JP: Early development and innervation of taste bud-bearing papillae on the rat tongue. J Comp Neurol 1991;304:172–186.
  4. Krimm RF: Factors that regulate embryonic gustatory development. BMC Neurosci 2007;8(suppl 3):S4.
  5. Lopez GF, Krimm RF: Refinement of innervation accuracy following initial targeting of peripheral gustatory fibers. J Neurobiol 2006;66:1033–1043.
  6. Nosrat IV, Lindskog S, Seiger A, Nosrat CA: Lingual BDNF and NT-3 mRNA expression patterns and their relation to innervation in the human tongue: similarities and differences compared with rodents. J Comp Neurol 2000;417:133–152.
  7. Nosrat CA, Ebendal T, Olson L: Differential expression of brain-derived neurotrophic factor and neurotrophin 3 mRNA in lingual papillae and taste buds indicates roles in gustatory and somatosensory innervation. J Comp Neurol 1996;376:587–602.
  8. Nosrat CA, Olson L: Brain-derived neurotrophic factor mRNA is expressed in the developing taste bud-bearing tongue papillae of rat. J Comp Neurol 1995;360:698–704.
  9. Nosrat IV, Agerman K, Marinescu A, Ernfors P, Nosrat CA: Lingual deficits in neurotrophin double knockout mice. J Neurocytol 2004;33:607–615.
  10. Nosrat CA, Blomlof J, ElShamy WM, Ernfors P, Olson L: Lingual deficits in BDNF and NT3 mutant mice leading to gustatory and somatosensory disturbances, respectively. Development 1997;124:1333–1342.
  11. Zhang C, Brandemihl A, Lau D, Lawton A, Oakley B: BDNF is required for the normal development of taste neurons in vivo. Neuroreport 1997;8:1013–1017.
  12. Ma L, Lopez GF, Krimm RF: Epithelial- derived brain-derived neurotrophic factor is required for gustatory neuron targeting during a critical developmental period. J Neurosci 2009;29:3354–3364.
  13. Ringstedt T, Ibanez CF, Nosrat CA: Role of brain-derived neurotrophic factor in target invasion in the gustatory system. J Neurosci 1999;19:3507–3518.
  14. Lopez GF, Krimm RF: Epithelial overexpression of BDNF and NT4 produces distinct gustatory axon morphologies that disrupt initial targeting. Dev Biol 2006;292:457–468.
  15. Krimm RF, Miller KK, Kitzman PH, Davis BM, Albers KM: Epithelial overexpression of BDNF or NT4 disrupts targeting of taste neurons that innervate the anterior tongue. Dev Biol 2001;232:508–521.
  16. Patel TD, Kramer I, Kucera J, Niederkofler V, Jessell TM, Arber S, Snider WD: Peripheral NT3 signaling is required for ETS protein expression and central patterning of proprioceptive sensory afferents. Neuron 2003;38:403–416.
  17. Markus A, Patel TD, Snider WD: Neurotrophic factors and axonal growth. Curr Opin Neurobiol 2002;12:523–531.
  18. Genc B, Ozdinler PH, Mendoza AE, Erzurumlu RS: A chemoattractant role for NT-3 in proprioceptive axon guidance. PLoS Biol 2004;2:e403.
  19. Ulupinar E, Jacquin MF, Erzurumlu RS: Differential effects of NGF and NT-3 on embryonic trigeminal axon growth patterns. J Comp Neurol 2000;425:202–218.
  20. Tessarollo L, Coppola V, Fritzsch B: NT-3 replacement with brain-derived neurotrophic factor redirects vestibular nerve fibers to the cochlea. J Neurosci 2004;24:2575–2584.
  21. Fritzsch B, Tessarollo L, Coppola E, Reichardt LF: Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance. Prog Brain Res 2004;146:265–278.
  22. LeMaster AM, Krimm RF, Davis BM, Noel T, Forbes ME, Johnson JE, Albers KM: Overexpression of brain-derived neurotrophic factor enhances sensory innervation and selectively increases neuron number. J Neurosci 1999;19:5919–5931.
  23. Tucker KL, Meyer M, Barde YA: Neurotrophins are required for nerve growth during development. Nat Neurosci 2001;4:29–37.
  24. Ming G, Lohof AM, Zheng JQ: Acute morphogenic and chemotropic effects of neurotrophins on cultured embryonic Xenopus spinal neurons. J Neurosci 1997;17:7860–7871.
  25. Mai J, Fok L, Gao H, Zhang X, Poo MM: Axon initiation and growth cone turning on bound protein gradients. J Neurosci 2009;29:7450–7458.
  26. Gehler S, Shaw AE, Sarmiere PD, Bamburg JR, Letourneau PC: Brain-derived neurotrophic factor regulation of retinal growth cone filopodial dynamics is mediated through actin depolymerizing factor/cofilin. J Neurosci 2004;24:10741–10749.
  27. O’Connor R, Tessier-Lavigne M: Identification of maxillary factor, a maxillary process-derived chemoattractant for developing trigeminal sensory axons. Neuron 1999;24:165–178.
  28. Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF: Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 1996;16:3123–3129.
  29. Conover JC, Erickson JT, Katz DM, Bianchi LM, Poueymirou WT, McClain J, Pan L, Helgren M, Ip NY, Boland P, et al: Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature 1995;375:235–238.
  30. Liu X, Ernfors P, Wu H, Jaenisch R: Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature 1995;375:238–241.
  31. Zhang X, Poo MM: Localized synaptic potentiation by BDNF requires local protein synthesis in the developing axon. Neuron 2002;36:675–688.
  32. Botchkarev VA, Yaar M, Peters EM, Raychaudhuri SP, Botchkareva NV, Marconi A, Raychaudhuri SK, Paus R, Pincelli C: Neurotrophins in skin biology and pathology. J Invest Dermatol 2006;126:1719–1727.
  33. de Carlos F, Cobo J, Germana G, Silos-Santiago I, Laura R, Haro JJ, Farinas I, Vega JA: Abnormal development of pacinian corpuscles in double trkB;trkC knockout mice. Neurosci Lett 2006;410:157–161.
  34. Kirstein M, Farinas I: Sensing life: regulation of sensory neuron survival by neurotrophins. Cell Mol Life Sci 2002;59:1787–1802.
  35. Tuttle R, O’Leary DD: Neurotrophins rapidly modulate growth cone response to the axon guidance molecule, collapsin-1. Mol Cell Neurosci 1998;11:1–8.
  36. Ming G, Song H, Berninger B, Inagaki N, Tessier-Lavigne M, Poo M: Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron 1999;23:139–148.
  37. Dontchev VD, Letourneau PC: Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. J Neurosci 2002;22:6659–6669.
  38. Yee CL, Jones KR, Finger TE: Brain-derived neurotrophic factor is present in adult mouse taste cells with synapses. J Comp Neurol 2003;459:15–24.
  39. Beidler LM, Smallman RL: Renewal of cells within taste buds. J Cell Biol 1965;27:263–272.
  40. Montavon P, Hellekant G, Farbman A: Immunohistochemical, electrophysiological, and electron microscopical study of rat fungiform taste buds after regeneration of chorda tympani through the non-gustatory lingual nerve. J Comp Neurol 1996;367:491–502.
  41. Oakley B: Reformation of taste buds by crossed sensory nerves in the rat’s tongue. Acta Physiol Scand 1970;79:88–94.
  42. Rochlin MW, Farbman AI: Trigeminal ganglion axons are repelled by their presumptive targets. J Neurosci 1998;18:6840–6852.
  43. Slavkin H, Nuckolls G, Shum L: Craniofacial development and patterning. Methods Mol Biol 2000;136:45–54.
  44. Mbiene JP, Farbman AI: Evidence for stimulus access to taste cells and nerves during development: an electron microscopic study. Microsc Res Tech 1993;26:94–105.
  45. Lumsden AG, Davies AM: Chemotropic effect of specific target epithelium in the developing mammalian nervous system. Nature 1986;323:538–539.
  46. Lumsden AG, Davies AM: Earliest sensory nerve fibres are guided to peripheral targets by attractants other than nerve growth factor. Nature 1983;306:786–788.
  47. Nosrat CA: Neurotrophic factors in the tongue: expression patterns, biological activity, relation to innervation and studies of neurotrophin knockout mice. Ann N Y Acad Sci 1998;855:28–49.
  48. Zou H, Ho C, Wong K, Tessier-Lavigne M: Axotomy-induced Smad1 activation promotes axonal growth in adult sensory neurons. J Neurosci 2009;29:7116–7123.
  49. Ozdinler PH, Ulupinar E, Erzurumlu RS: Dose and age-dependent axonal responses of embryonic trigeminal neurons to localized NGF via p75NTR receptor. J Neurobiol 2005;62:189–206.
  50. Griffin CG, Letourneau PC: Rapid retraction of neurites by sensory neurons in response to increased concentrations of nerve growth factor. J Cell Biol 1980;86:156–161.
  51. Conti AM, Fischer SJ, Windebank AJ: Inhibition of axonal growth from sensory neurons by excess nerve growth factor. Ann Neurol 1997;42:838–846.
  52. Xu B, Michalski B, Racine RJ, Fahnestock M: The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. Neuroscience 2004;126:521–531.
  53. Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L, Duan S, Lu B: Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2010;13:302–309.
  54. Song HJ, Poo MM: Signal transduction underlying growth cone guidance by diffusible factors. Curr Opin Neurobiol 1999;9:355–363.
  55. Mortimer D, Pujic Z, Vaughan T, Thompson AW, Feldner J, Vetter I, Goodhill GJ: Axon guidance by growth-rate modulation. Proc Natl Acad Sci USA 1998;107:5202–5207.

    External Resources

  56. Patel TD, Jackman A, Rice FL, Kucera J, Snider WD: Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 2000;25:345–357.
  57. Hopker VH, Shewan D, Tessier-Lavigne M, Poo M, Holt C: Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 1999;401:69–73.
  58. Vilbig R, Cosmano J, Giger R, Rochlin MW: Distinct roles for Sema3A, Sema3F, and an unidentified trophic factor in controlling the advance of geniculate axons to gustatory lingual epithelium. J Neurocytol 2004;33:591–606.
  59. Dillon TE, Saldanha J, Giger R, Verhaagen J, Rochlin MW: Sema3A regulates the timing of target contact by cranial sensory axons. J Comp Neurol 2004;470:13–24.
  60. Rochlin MW, O’Connor R, Giger RJ, Verhaagen J, Farbman AI: Comparison of neurotrophin and repellent sensitivities of early embryonic geniculate and trigeminal axons. J Comp Neurol 2000;422:579–593.
  61. Gordon T. The role of neurotrophic factors in nerve regeneration. Neurosurg Focus 2009;26:E3.
  62. Miller IJ Jr, Gomez MM, Lubarsky EH. Distribution of the facial nerve to taste receptors in the rat Chem Senses Flavor 1978;3:397–411.
  63. Miller IJ Jr, Spangler KM. Taste bud distribution and innervation on the palate of the rat. Chem Senses 1982;7:99–108.
  64. Nosrat CA, Olson L. Changes in neurotrophin-3 messenger RNA expression patterns in the prenatal rat tongue suggest guidance of developing somatosensory nerves to their final targets. Cell Tissue Res 1998;292:619–623.
  65. Streiner DL. Maintaining standards: differences between the standard deviation and standard error, and when to use each. Can J Psychiatry 1996;41:498–502.

 goto top of outline Author Contacts

Assoc. Prof. M. William Rochlin
Loyola University Chicago, Biology Department, LSB 317B
1032 W. Sheridan Road
Chicago, IL 60660 (USA)
Tel. +1 773 508 2450, Fax +1 773 508 3646, E-Mail

 goto top of outline Article Information

Received: October 13, 2009
Accepted after revision: April 15, 2010
Published online: July 20, 2010
Number of Print Pages : 13
Number of Figures : 4, Number of Tables : 0, Number of References : 65

 goto top of outline Publication Details

Developmental Neuroscience

Vol. 32, No. 3, Year 2010 (Cover Date: August 2010)

Journal Editor: Levison S.W. (Newark, N.J.)
ISSN: 0378-5866 (Print), eISSN: 1421-9859 (Online)

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