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. 1996 Dec 2;15(23):6385–6393.

Expression and function of TrkB variants in developing sensory neurons.

N Ninkina 1, J Adu 1, A Fischer 1, L G Piñón 1, V L Buchman 1, A M Davies 1
PMCID: PMC452462  PMID: 8978665

Abstract

Mouse trigeminal neurons survive independently of neurotrophins when their axons are growing to their targets, and are then transiently supported by BDNF before becoming NGF dependent. During the stage of neurotrophin independence, transcripts encoding the BDNF receptor, TrkB, were expressed at very low levels. During the stage of BDNF dependence, high levels of a transcript encoding a receptor with the catalytic tyrosine kinase domain were expressed. Although the levels of this transcript fell as the neurons lost responsiveness to BDNF, there were concomitant increases in the expression of transcripts encoding TrkB variants lacking the kinase domain. Analysis of RNA from purified neurons showed that all of these transcripts were present in neurons. BDNF and NGF up-regulated the expression of these transcripts early in development but had little effect later on. To test whether truncated TrkB modulates BDNF signalling via catalytic TrkB, we injected TrkB expression plasmids into NGF-dependent sympathetic neurons. Whereas expression of catalytic TrkB alone conferred a BDNF survival response, co-expression of non-catalytic TrkB substantially reduced this response. Our results suggest that BDNF responsiveness in sensory neurons during development is modulated by the relative levels of catalytic and non-catalytic TrkB.

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Selected References

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  1. Allendoerfer K. L., Cabelli R. J., Escandón E., Kaplan D. R., Nikolics K., Shatz C. J. Regulation of neurotrophin receptors during the maturation of the mammalian visual system. J Neurosci. 1994 Mar;14(3 Pt 2):1795–1811. doi: 10.1523/JNEUROSCI.14-03-01795.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allsopp T. E., Wyatt S., Paterson H. F., Davies A. M. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell. 1993 Apr 23;73(2):295–307. doi: 10.1016/0092-8674(93)90230-n. [DOI] [PubMed] [Google Scholar]
  3. Armanini M. P., McMahon S. B., Sutherland J., Shelton D. L., Phillips H. S. Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS. Eur J Neurosci. 1995 Jun 1;7(6):1403–1409. doi: 10.1111/j.1460-9568.1995.tb01132.x. [DOI] [PubMed] [Google Scholar]
  4. Arumäe U., Pirvola U., Palgi J., Kiema T. R., Palm K., Moshnyakov M., Ylikoski J., Saarma M. Neurotrophins and their receptors in rat peripheral trigeminal system during maxillary nerve growth. J Cell Biol. 1993 Sep;122(5):1053–1065. doi: 10.1083/jcb.122.5.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol. 1994 Nov;25(11):1386–1403. doi: 10.1002/neu.480251107. [DOI] [PubMed] [Google Scholar]
  6. Beck K. D., Lamballe F., Klein R., Barbacid M., Schauwecker P. E., McNeill T. H., Finch C. E., Hefti F., Day J. R. Induction of noncatalytic TrkB neurotrophin receptors during axonal sprouting in the adult hippocampus. J Neurosci. 1993 Sep;13(9):4001–4014. doi: 10.1523/JNEUROSCI.13-09-04001.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Biffo S., Offenhäuser N., Carter B. D., Barde Y. A. Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development. 1995 Aug;121(8):2461–2470. doi: 10.1242/dev.121.8.2461. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Buchman V. L., Sporn M., Davies A. M. Role of transforming growth factor-beta isoforms in regulating the expression of nerve growth factor and neurotrophin-3 mRNA levels in embryonic cutaneous cells at different stages of development. Development. 1994 Jun;120(6):1621–1629. doi: 10.1242/dev.120.6.1621. [DOI] [PubMed] [Google Scholar]
  10. Buj-Bello A., Pinon L. G., Davies A. M. The survival of NGF-dependent but not BDNF-dependent cranial sensory neurons is promoted by several different neurotrophins early in their development. Development. 1994 Jun;120(6):1573–1580. doi: 10.1242/dev.120.6.1573. [DOI] [PubMed] [Google Scholar]
  11. Conover J. C., Erickson J. T., Katz D. M., Bianchi L. M., Poueymirou W. T., McClain J., Pan L., Helgren M., Ip N. Y., Boland P. Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature. 1995 May 18;375(6528):235–238. doi: 10.1038/375235a0. [DOI] [PubMed] [Google Scholar]
  12. Davies A. M., Bandtlow C., Heumann R., Korsching S., Rohrer H., Thoenen H. Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor. 1987 Mar 26-Apr 1Nature. 326(6111):353–358. doi: 10.1038/326353a0. [DOI] [PubMed] [Google Scholar]
  13. Davies A. M., Horton A., Burton L. E., Schmelzer C., Vandlen R., Rosenthal A. Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. J Neurosci. 1993 Nov;13(11):4961–4967. doi: 10.1523/JNEUROSCI.13-11-04961.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Davies A. M. The role of neurotrophins in the developing nervous system. J Neurobiol. 1994 Nov;25(11):1334–1348. doi: 10.1002/neu.480251103. [DOI] [PubMed] [Google Scholar]
  15. Davies A. M. The survival and growth of embryonic proprioceptive neurons is promoted by a factor present in skeletal muscle. Dev Biol. 1986 May;115(1):56–67. doi: 10.1016/0012-1606(86)90227-7. [DOI] [PubMed] [Google Scholar]
  16. Davies A. M., Wyatt S., Nishimura M., Phillips H. NGF receptor expression in sensory neurons develops normally in embryos lacking NGF. Dev Biol. 1995 Oct;171(2):434–438. doi: 10.1006/dbio.1995.1293. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Eide F. F., Vining E. R., Eide B. L., Zang K., Wang X. Y., Reichardt L. F. Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci. 1996 May 15;16(10):3123–3129. doi: 10.1523/JNEUROSCI.16-10-03123.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ernfors P., Lee K. F., Jaenisch R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature. 1994 Mar 10;368(6467):147–150. doi: 10.1038/368147a0. [DOI] [PubMed] [Google Scholar]
  20. Ernfors Patrik, Merlio Jean-Phillipe, Persson Håkan. Cells Expressing mRNA for Neurotrophins and their Receptors During Embryonic Rat Development. Eur J Neurosci. 1992 Oct;4(11):1140–1158. doi: 10.1111/j.1460-9568.1992.tb00141.x. [DOI] [PubMed] [Google Scholar]
  21. Escandón E., Soppet D., Rosenthal A., Mendoza-Ramírez J. L., Szönyi E., Burton L. E., Henderson C. E., Parada L. F., Nikolics K. Regulation of neurotrophin receptor expression during embryonic and postnatal development. J Neurosci. 1994 Apr;14(4):2054–2068. doi: 10.1523/JNEUROSCI.14-04-02054.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Frisén J., Verge V. M., Fried K., Risling M., Persson H., Trotter J., Hökfelt T., Lindholm D. Characterization of glial trkB receptors: differential response to injury in the central and peripheral nervous systems. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):4971–4975. doi: 10.1073/pnas.90.11.4971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Funakoshi H., Frisén J., Barbany G., Timmusk T., Zachrisson O., Verge V. M., Persson H. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 1993 Oct;123(2):455–465. doi: 10.1083/jcb.123.2.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jing S., Tapley P., Barbacid M. Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron. 1992 Dec;9(6):1067–1079. doi: 10.1016/0896-6273(92)90066-m. [DOI] [PubMed] [Google Scholar]
  25. Jones K. R., Fariñas I., Backus C., Reichardt L. F. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell. 1994 Mar 25;76(6):989–999. doi: 10.1016/0092-8674(94)90377-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kaplan D. R., Stephens R. M. Neurotrophin signal transduction by the Trk receptor. J Neurobiol. 1994 Nov;25(11):1404–1417. doi: 10.1002/neu.480251108. [DOI] [PubMed] [Google Scholar]
  27. Klein R., Conway D., Parada L. F., Barbacid M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell. 1990 May 18;61(4):647–656. doi: 10.1016/0092-8674(90)90476-u. [DOI] [PubMed] [Google Scholar]
  28. Klein R., Martin-Zanca D., Barbacid M., Parada L. F. Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. Development. 1990 Aug;109(4):845–850. doi: 10.1242/dev.109.4.845. [DOI] [PubMed] [Google Scholar]
  29. Klein R., Parada L. F., Coulier F., Barbacid M. trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. EMBO J. 1989 Dec 1;8(12):3701–3709. doi: 10.1002/j.1460-2075.1989.tb08545.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Klein R. Role of neurotrophins in mouse neuronal development. FASEB J. 1994 Jul;8(10):738–744. doi: 10.1096/fasebj.8.10.8050673. [DOI] [PubMed] [Google Scholar]
  31. Knüsel B., Rabin S. J., Hefti F., Kaplan D. R. Regulated neurotrophin receptor responsiveness during neuronal migrationand early differentiation. J Neurosci. 1994 Mar;14(3 Pt 2):1542–1554. doi: 10.1523/JNEUROSCI.14-03-01542.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lamballe F., Tapley P., Barbacid M. trkC encodes multiple neurotrophin-3 receptors with distinct biological properties and substrate specificities. EMBO J. 1993 Aug;12(8):3083–3094. doi: 10.1002/j.1460-2075.1993.tb05977.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Liu X., Ernfors P., Wu H., Jaenisch R. Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature. 1995 May 18;375(6528):238–241. doi: 10.1038/375238a0. [DOI] [PubMed] [Google Scholar]
  34. Martin-Zanca D., Oskam R., Mitra G., Copeland T., Barbacid M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol Cell Biol. 1989 Jan;9(1):24–33. doi: 10.1128/mcb.9.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Morse J. K., Wiegand S. J., Anderson K., You Y., Cai N., Carnahan J., Miller J., DiStefano P. S., Altar C. A., Lindsay R. M. Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection. J Neurosci. 1993 Oct;13(10):4146–4156. doi: 10.1523/JNEUROSCI.13-10-04146.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Okazawa H., Kamei M., Kanazawa I. Molecular cloning and expression of a novel truncated form of chicken trkC. FEBS Lett. 1993 Aug 23;329(1-2):171–177. doi: 10.1016/0014-5793(93)80216-h. [DOI] [PubMed] [Google Scholar]
  38. Paul G., Davies A. M. Trigeminal sensory neurons require extrinsic signals to switch neurotrophin dependence during the early stages of target field innervation. Dev Biol. 1995 Oct;171(2):590–605. doi: 10.1006/dbio.1995.1307. [DOI] [PubMed] [Google Scholar]
  39. Piñon L. G., Minichiello L., Klein R., Davies A. M. Timing of neuronal death in trkA, trkB and trkC mutant embryos reveals developmental changes in sensory neuron dependence on Trk signalling. Development. 1996 Oct;122(10):3255–3261. doi: 10.1242/dev.122.10.3255. [DOI] [PubMed] [Google Scholar]
  40. Rudge J. S., Li Y., Pasnikowski E. M., Mattsson K., Pan L., Yancopoulos G. D., Wiegand S. J., Lindsay R. M., Ip N. Y. Neurotrophic factor receptors and their signal transduction capabilities in rat astrocytes. Eur J Neurosci. 1994 May 1;6(5):693–705. doi: 10.1111/j.1460-9568.1994.tb00981.x. [DOI] [PubMed] [Google Scholar]
  41. Tsoulfas P., Soppet D., Escandon E., Tessarollo L., Mendoza-Ramirez J. L., Rosenthal A., Nikolics K., Parada L. F. The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells. Neuron. 1993 May;10(5):975–990. doi: 10.1016/0896-6273(93)90212-a. [DOI] [PubMed] [Google Scholar]
  42. Valenzuela D. M., Maisonpierre P. C., Glass D. J., Rojas E., Nuñez L., Kong Y., Gies D. R., Stitt T. N., Ip N. Y., Yancopoulos G. D. Alternative forms of rat TrkC with different functional capabilities. Neuron. 1993 May;10(5):963–974. doi: 10.1016/0896-6273(93)90211-9. [DOI] [PubMed] [Google Scholar]
  43. Vogel K. S., Davies A. M. Heterotopic transplantation of presumptive placodal ectoderm changes the fate of sensory neuron precursors. Development. 1993 Sep;119(1):263–276. doi: 10.1242/dev.119.1.263. [DOI] [PubMed] [Google Scholar]
  44. Vogel K. S., Davies A. M. The duration of neurotrophic factor independence in early sensory neurons is matched to the time course of target field innervation. Neuron. 1991 Nov;7(5):819–830. doi: 10.1016/0896-6273(91)90284-7. [DOI] [PubMed] [Google Scholar]
  45. Wyatt S., Davies A. M. Regulation of expression of mRNAs encoding the nerve growth factor receptors p75 and trkA in developing sensory neurons. Development. 1993 Nov;119(3):635–648. doi: 10.1242/dev.119.3.635. [DOI] [PubMed] [Google Scholar]
  46. Wyatt S., Davies A. M. Regulation of nerve growth factor receptor gene expression in sympathetic neurons during development. J Cell Biol. 1995 Sep;130(6):1435–1446. doi: 10.1083/jcb.130.6.1435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wyatt S., Shooter E. M., Davies A. M. Expression of the NGF receptor gene in sensory neurons and their cutaneous targets prior to and during innervation. Neuron. 1990 Mar;4(3):421–427. doi: 10.1016/0896-6273(90)90054-j. [DOI] [PubMed] [Google Scholar]

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