Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1996 Jul 2;134(2):487–497. doi: 10.1083/jcb.134.2.487

Cutaneous overexpression of NT-3 increases sensory and sympathetic neuron number and enhances touch dome and hair follicle innervation

PMCID: PMC2120868  PMID: 8707832

Abstract

Target-derived influences of nerve growth factor on neuronal survival and differentiation are well documented, though effects of other neurotrophins are less clear. To examine the influence of NT-3 neurotrophin overexpression in a target tissue of sensory and sympathetic neurons, transgenic mice were isolated that overexpress NT- 3 in the epidermis. Overexpression of NT-3 led to a 42% increase in the number of dorsal root ganglia sensory neurons, a 70% increase in the number of trigeminal sensory neurons, and a 32% increase in sympathetic neurons. Elevated NT-3 also caused enlargement of touch dome mechanoreceptor units, sensory end organs innervated by slowly adapting type 1 (SA1) neurons. The enlarged touch dome units of the transgenics had an increased number of associated Merkel cells, cells at which SA1s terminate. An additional alteration of skin innervation in NT-3 transgenics was an increased density of myelinated circular endings associated with the piloneural complex. The enhancement of innervation to the skin was accompanied by a doubling in the number of sensory neurons expressing trkC. In addition, measures of nerve fibers in cross- sectional profiles of cutaneous saphenous nerves of transgenics showed a 60% increase in myelinated fibers. These results indicate that in vivo overexpression of NT-3 by the epidermis enhances the number of sensory and sympathetic neurons and the development of selected sensory endings of the skin.

Full Text

The Full Text of this article is available as a PDF (5.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Airaksinen M. S., Koltzenburg M., Lewin G. R., Masu Y., Helbig C., Wolf E., Brem G., Toyka K. V., Thoenen H., Meyer M. Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. Neuron. 1996 Feb;16(2):287–295. doi: 10.1016/s0896-6273(00)80047-1. [DOI] [PubMed] [Google Scholar]
  2. Albers K. M., Wright D. E., Davis B. M. Overexpression of nerve growth factor in epidermis of transgenic mice causes hypertrophy of the peripheral nervous system. J Neurosci. 1994 Mar;14(3 Pt 2):1422–1432. doi: 10.1523/JNEUROSCI.14-03-01422.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barres B. A., Raff M. C., Gaese F., Bartke I., Dechant G., Barde Y. A. A crucial role for neurotrophin-3 in oligodendrocyte development. Nature. 1994 Jan 27;367(6461):371–375. doi: 10.1038/367371a0. [DOI] [PubMed] [Google Scholar]
  4. Berkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., Rosenthal A. Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron. 1991 Nov;7(5):857–866. doi: 10.1016/0896-6273(91)90287-a. [DOI] [PubMed] [Google Scholar]
  5. Birren S. J., Lo L., Anderson D. J. Sympathetic neuroblasts undergo a developmental switch in trophic dependence. Development. 1993 Nov;119(3):597–610. doi: 10.1242/dev.119.3.597. [DOI] [PubMed] [Google Scholar]
  6. Buchman V. L., Davies A. M. Different neurotrophins are expressed and act in a developmental sequence to promote the survival of embryonic sensory neurons. Development. 1993 Jul;118(3):989–1001. doi: 10.1242/dev.118.3.989. [DOI] [PubMed] [Google Scholar]
  7. Byrne C., Tainsky M., Fuchs E. Programming gene expression in developing epidermis. Development. 1994 Sep;120(9):2369–2383. doi: 10.1242/dev.120.9.2369. [DOI] [PubMed] [Google Scholar]
  8. Chao M. V., Bothwell M. A., Ross A. H., Koprowski H., Lanahan A. A., Buck C. R., Sehgal A. Gene transfer and molecular cloning of the human NGF receptor. Science. 1986 Apr 25;232(4749):518–521. doi: 10.1126/science.3008331. [DOI] [PubMed] [Google Scholar]
  9. Chen S. Y., Gerson S., Meyer J. The fusion of Merkel cell granules with a synapse-like structure. J Invest Dermatol. 1973 Nov;61(5):290–292. doi: 10.1111/1523-1747.ep12676510. [DOI] [PubMed] [Google Scholar]
  10. Coggeshall R. E., Chung K., Greenwood D., Hulsebosch C. E. An empirical method for converting nucleolar counts to neuronal numbers. J Neurosci Methods. 1984 Dec;12(2):125–132. doi: 10.1016/0165-0270(84)90011-6. [DOI] [PubMed] [Google Scholar]
  11. Coggeshall R. E., La Forte R., Klein C. M. Calibration of methods for determining numbers of dorsal root ganglion cells. J Neurosci Methods. 1990 Dec;35(3):187–194. doi: 10.1016/0165-0270(90)90123-w. [DOI] [PubMed] [Google Scholar]
  12. Crowley C., Spencer S. D., Nishimura M. C., Chen K. S., Pitts-Meek S., Armanini M. P., Ling L. H., McMahon S. B., Shelton D. L., Levinson A. D. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell. 1994 Mar 25;76(6):1001–1011. doi: 10.1016/0092-8674(94)90378-6. [DOI] [PubMed] [Google Scholar]
  13. Curtis R., Adryan K. M., Stark J. L., Park J. S., Compton D. L., Weskamp G., Huber L. J., Chao M. V., Jaenisch R., Lee K. F. Differential role of the low affinity neurotrophin receptor (p75) in retrograde axonal transport of the neurotrophins. Neuron. 1995 Jun;14(6):1201–1211. doi: 10.1016/0896-6273(95)90267-8. [DOI] [PubMed] [Google Scholar]
  14. Davies A. M., Thoenen H., Barde Y. A. The response of chick sensory neurons to brain-derived neurotrophic factor. J Neurosci. 1986 Jul;6(7):1897–1904. doi: 10.1523/JNEUROSCI.06-07-01897.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Davies A., Lumsden A. Relation of target encounter and neuronal death to nerve growth factor responsiveness in the developing mouse trigeminal ganglion. J Comp Neurol. 1984 Feb 10;223(1):124–137. doi: 10.1002/cne.902230110. [DOI] [PubMed] [Google Scholar]
  16. Dechant G., Rodríguez-Tébar A., Kolbeck R., Barde Y. A. Specific high-affinity receptors for neurotrophin-3 on sympathetic neurons. J Neurosci. 1993 Jun;13(6):2610–2616. doi: 10.1523/JNEUROSCI.13-06-02610.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. DiCicco-Bloom E., Friedman W. J., Black I. B. NT-3 stimulates sympathetic neuroblast proliferation by promoting precursor survival. Neuron. 1993 Dec;11(6):1101–1111. doi: 10.1016/0896-6273(93)90223-e. [DOI] [PubMed] [Google Scholar]
  18. DiStefano P. S., Friedman B., Radziejewski C., Alexander C., Boland P., Schick C. M., Lindsay R. M., Wiegand S. J. The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron. 1992 May;8(5):983–993. doi: 10.1016/0896-6273(92)90213-w. [DOI] [PubMed] [Google Scholar]
  19. Dixon J. E., McKinnon D. Expression of the trk gene family of neurotrophin receptors in prevertebral sympathetic ganglia. Brain Res Dev Brain Res. 1994 Feb 18;77(2):177–182. doi: 10.1016/0165-3806(94)90194-5. [DOI] [PubMed] [Google Scholar]
  20. Edwards R. H., Rutter W. J., Hanahan D. Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets. Cell. 1989 Jul 14;58(1):161–170. doi: 10.1016/0092-8674(89)90412-1. [DOI] [PubMed] [Google Scholar]
  21. Ernfors P., Lee K. F., Kucera J., Jaenisch R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell. 1994 May 20;77(4):503–512. doi: 10.1016/0092-8674(94)90213-5. [DOI] [PubMed] [Google Scholar]
  22. Fariñas I., Jones K. R., Backus C., Wang X. Y., Reichardt L. F. Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Nature. 1994 Jun 23;369(6482):658–661. doi: 10.1038/369658a0. [DOI] [PubMed] [Google Scholar]
  23. Gottschaldt K. M., Vahle-Hinz C. Merkel cell receptors: structure and transducer function. Science. 1981 Oct 9;214(4517):183–186. doi: 10.1126/science.7280690. [DOI] [PubMed] [Google Scholar]
  24. Hallbök F., Ibáez C. F., Persson H. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron. 1991 May;6(5):845–858. doi: 10.1016/0896-6273(91)90180-8. [DOI] [PubMed] [Google Scholar]
  25. Harding A. J., Halliday G. M., Cullen K. Practical considerations for the use of the optical disector in estimating neuronal number. J Neurosci Methods. 1994 Jan;51(1):83–89. doi: 10.1016/0165-0270(94)90028-0. [DOI] [PubMed] [Google Scholar]
  26. Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F., Chao M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678–683. doi: 10.1038/350678a0. [DOI] [PubMed] [Google Scholar]
  27. Hohn A., Leibrock J., Bailey K., Barde Y. A. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature. 1990 Mar 22;344(6264):339–341. doi: 10.1038/344339a0. [DOI] [PubMed] [Google Scholar]
  28. Hory-Lee F., Russell M., Lindsay R. M., Frank E. Neurotrophin 3 supports the survival of developing muscle sensory neurons in culture. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2613–2617. doi: 10.1073/pnas.90.7.2613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ip N. Y., Ibáez C. F., Nye S. H., McClain J., Jones P. F., Gies D. R., Belluscio L., Le Beau M. M., Espinosa R., 3rd, Squinto S. P. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3060–3064. doi: 10.1073/pnas.89.7.3060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ip N. Y., Stitt T. N., Tapley P., Klein R., Glass D. J., Fandl J., Greene L. A., Barbacid M., Yancopoulos G. D. Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells. Neuron. 1993 Feb;10(2):137–149. doi: 10.1016/0896-6273(93)90306-c. [DOI] [PubMed] [Google Scholar]
  31. Kaplan D. R., Hempstead B. L., Martin-Zanca D., Chao M. V., Parada L. F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science. 1991 Apr 26;252(5005):554–558. doi: 10.1126/science.1850549. [DOI] [PubMed] [Google Scholar]
  32. Klein R., Jing S. Q., Nanduri V., O'Rourke E., Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189–197. doi: 10.1016/0092-8674(91)90419-y. [DOI] [PubMed] [Google Scholar]
  33. Klein R., Smeyne R. J., Wurst W., Long L. K., Auerbach B. A., Joyner A. L., Barbacid M. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell. 1993 Oct 8;75(1):113–122. [PubMed] [Google Scholar]
  34. Korsching S., Thoenen H. Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: correlation with density of sympathetic innervation. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3513–3516. doi: 10.1073/pnas.80.11.3513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kucera J., Ernfors P., Walro J., Jaenisch R. Reduction in the number of spinal motor neurons in neurotrophin-3-deficient mice. Neuroscience. 1995 Nov;69(1):321–330. doi: 10.1016/0306-4522(95)00221-4. [DOI] [PubMed] [Google Scholar]
  36. Kucera J., Fan G., Jaenisch R., Linnarsson S., Ernfors P. Dependence of developing group Ia afferents on neurotrophin-3. J Comp Neurol. 1995 Dec 11;363(2):307–320. doi: 10.1002/cne.903630211. [DOI] [PubMed] [Google Scholar]
  37. Lamballe F., Klein R., Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991 Sep 6;66(5):967–979. doi: 10.1016/0092-8674(91)90442-2. [DOI] [PubMed] [Google Scholar]
  38. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., Barde Y. A. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989 Sep 14;341(6238):149–152. doi: 10.1038/341149a0. [DOI] [PubMed] [Google Scholar]
  39. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987 Sep 4;237(4819):1154–1162. doi: 10.1126/science.3306916. [DOI] [PubMed] [Google Scholar]
  40. Lindsay R. M., Rohrer H. Placodal sensory neurons in culture: nodose ganglion neurons are unresponsive to NGF, lack NGF receptors but are supported by a liver-derived neurotrophic factor. Dev Biol. 1985 Nov;112(1):30–48. doi: 10.1016/0012-1606(85)90116-2. [DOI] [PubMed] [Google Scholar]
  41. Maisonpierre P. C., Belluscio L., Squinto S., Ip N. Y., Furth M. E., Lindsay R. M., Yancopoulos G. D. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. doi: 10.1126/science.247.4949.1446. [DOI] [PubMed] [Google Scholar]
  42. McMahon S. B., Armanini M. P., Ling L. H., Phillips H. S. Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron. 1994 May;12(5):1161–1171. doi: 10.1016/0896-6273(94)90323-9. [DOI] [PubMed] [Google Scholar]
  43. Meakin S. O., Shooter E. M. The nerve growth factor family of receptors. Trends Neurosci. 1992 Sep;15(9):323–331. doi: 10.1016/0166-2236(92)90047-c. [DOI] [PubMed] [Google Scholar]
  44. Merlio J. P., Ernfors P., Jaber M., Persson H. Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system. Neuroscience. 1992 Dec;51(3):513–532. doi: 10.1016/0306-4522(92)90292-a. [DOI] [PubMed] [Google Scholar]
  45. Mu X., Silos-Santiago I., Carroll S. L., Snider W. D. Neurotrophin receptor genes are expressed in distinct patterns in developing dorsal root ganglia. J Neurosci. 1993 Sep;13(9):4029–4041. doi: 10.1523/JNEUROSCI.13-09-04029.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Nurse C. A., Diamond J. A fluorescent microscopic study of the development of rat touch domes and their Merkel cells. Neuroscience. 1984 Feb;11(2):509–520. doi: 10.1016/0306-4522(84)90041-1. [DOI] [PubMed] [Google Scholar]
  47. Nurse C. A., Macintyre L., Diamond J. A quantitative study of the time course of the reduction in Merkel cell number within denervated rat touch domes. Neuroscience. 1984 Feb;11(2):521–533. doi: 10.1016/0306-4522(84)90042-3. [DOI] [PubMed] [Google Scholar]
  48. Offenhäuser N., Böhm-Matthaei R., Tsoulfas P., Parada L., Meyer M. Developmental regulation of full-length trkC in the rat sciatic nerve. Eur J Neurosci. 1995 May 1;7(5):917–925. doi: 10.1111/j.1460-9568.1995.tb01079.x. [DOI] [PubMed] [Google Scholar]
  49. Pasche F., Mérot Y., Carraux P., Saurat J. H. Relationship between Merkel cells and nerve endings during embryogenesis in the mouse epidermis. J Invest Dermatol. 1990 Sep;95(3):247–251. doi: 10.1111/1523-1747.ep12484847. [DOI] [PubMed] [Google Scholar]
  50. Rice F. L., Kinnman E., Aldskogius H., Johansson O., Arvidsson J. The innervation of the mystacial pad of the rat as revealed by PGP 9.5 immunofluorescence. J Comp Neurol. 1993 Nov 15;337(3):366–385. doi: 10.1002/cne.903370303. [DOI] [PubMed] [Google Scholar]
  51. Rose R. D., Rohrlich D. Counting sectioned cells via mathematical reconstruction. J Comp Neurol. 1987 Sep 15;263(3):365–386. doi: 10.1002/cne.902630305. [DOI] [PubMed] [Google Scholar]
  52. Rosenthal A., Goeddel D. V., Nguyen T., Lewis M., Shih A., Laramee G. R., Nikolics K., Winslow J. W. Primary structure and biological activity of a novel human neurotrophic factor. Neuron. 1990 May;4(5):767–773. doi: 10.1016/0896-6273(90)90203-r. [DOI] [PubMed] [Google Scholar]
  53. Ruit K. G., Elliott J. L., Osborne P. A., Yan Q., Snider W. D. Selective dependence of mammalian dorsal root ganglion neurons on nerve growth factor during embryonic development. Neuron. 1992 Mar;8(3):573–587. doi: 10.1016/0896-6273(92)90284-k. [DOI] [PubMed] [Google Scholar]
  54. Schecterson L. C., Bothwell M. Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons. Neuron. 1992 Sep;9(3):449–463. doi: 10.1016/0896-6273(92)90183-e. [DOI] [PubMed] [Google Scholar]
  55. Shelton D. L., Reichardt L. F. Expression of the beta-nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7951–7955. doi: 10.1073/pnas.81.24.7951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Smith K. R., Jr The structure and function of the Haarscheibe. J Comp Neurol. 1967 Dec;131(4):459–474. doi: 10.1002/cne.901310406. [DOI] [PubMed] [Google Scholar]
  57. Snider W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell. 1994 Jun 3;77(5):627–638. doi: 10.1016/0092-8674(94)90048-5. [DOI] [PubMed] [Google Scholar]
  58. Tan J., Simpson J. I., Voogd J. Anatomical compartments in the white matter of the rabbit flocculus. J Comp Neurol. 1995 May 22;356(1):1–22. doi: 10.1002/cne.903560102. [DOI] [PubMed] [Google Scholar]
  59. Thoenen H., Bandtlow C., Heumann R. The physiological function of nerve growth factor in the central nervous system: comparison with the periphery. Rev Physiol Biochem Pharmacol. 1987;109:145–178. doi: 10.1007/BFb0031026. [DOI] [PubMed] [Google Scholar]
  60. Vassar R., Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev. 1991 May;5(5):714–727. doi: 10.1101/gad.5.5.714. [DOI] [PubMed] [Google Scholar]
  61. Verdi J. M., Anderson D. J. Neurotrophins regulate sequential changes in neurotrophin receptor expression by sympathetic neuroblasts. Neuron. 1994 Dec;13(6):1359–1372. doi: 10.1016/0896-6273(94)90421-9. [DOI] [PubMed] [Google Scholar]
  62. West M. J. New stereological methods for counting neurons. Neurobiol Aging. 1993 Jul-Aug;14(4):275–285. doi: 10.1016/0197-4580(93)90112-o. [DOI] [PubMed] [Google Scholar]
  63. Yancopoulos G. D., Maisonpierre P. C., Ip N. Y., Aldrich T. H., Belluscio L., Boulton T. G., Cobb M. H., Squinto S. P., Furth M. E. Neurotrophic factors, their receptors, and the signal transduction pathways they activate. Cold Spring Harb Symp Quant Biol. 1990;55:371–379. doi: 10.1101/sqb.1990.055.01.038. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES