Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Aug 16;91(17):7839–7843. doi: 10.1073/pnas.91.17.7839

Leukemia inhibitory factor induces neurotransmitter switching in transgenic mice.

B A Bamber 1, B A Masters 1, G W Hoyle 1, R L Brinster 1, R D Palmiter 1
PMCID: PMC44499  PMID: 7914698

Abstract

Leukemia inhibitory factor (LIF) is a cytokine growth factor that induces rat sympathetic neurons to switch their neurotransmitter phenotype from noradrenergic to cholinergic in vitro. To test whether LIF can influence neuronal differentiation in vivo, we generated transgenic mice that expressed LIF in pancreatic islets under the control of the insulin promoter and evaluated the neurotransmitter phenotype of the pancreatic sympathetic innervation. We also used the insulin promoter to coexpress nerve growth factor in the islets, which greatly increased the density of sympathetic innervation and facilitated analysis of the effects of LIF. Our data demonstrate that tyrosine hydroxylase and catecholamines declined and choline acetyltransferase increased in response to LIF. We conclude that LIF can induce neurotransmitter switching of sympathetic neurons in vivo.

Full text

PDF
7839

Images in this article

7841Image
on p.7841
7841Image
on p.7841
7842Image
on p.7842
7843Image
on p.7843

Selected References

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

  1. Adler J. E., Black I. B. Sympathetic neuron density differentially regulates transmitter phenotypic expression in culture. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4296–4300. doi: 10.1073/pnas.82.12.4296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chun L. L., Patterson P. H. Role of nerve growth factor in the development of rat sympathetic neurons in vitro. III. Effect on acetylcholine production. J Cell Biol. 1977 Dec;75(3):712–718. doi: 10.1083/jcb.75.3.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. De la Torre J. C. An improved approach to histofluorescence using the SPG method for tissue monoamines. J Neurosci Methods. 1980 Oct;3(1):1–5. doi: 10.1016/0165-0270(80)90029-1. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Fonnum F. A rapid radiochemical method for the determination of choline acetyltransferase. J Neurochem. 1975 Feb;24(2):407–409. doi: 10.1111/j.1471-4159.1975.tb11895.x. [DOI] [PubMed] [Google Scholar]
  7. Gearing D. P., Gough N. M., King J. A., Hilton D. J., Nicola N. A., Simpson R. J., Nice E. C., Kelso A., Metcalf D. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J. 1987 Dec 20;6(13):3995–4002. doi: 10.1002/j.1460-2075.1987.tb02742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Haycock J. W. Quantitation of tyrosine hydroxylase, protein levels: spot immunolabeling with an affinity-purified antibody. Anal Biochem. 1989 Sep;181(2):259–266. doi: 10.1016/0003-2697(89)90240-6. [DOI] [PubMed] [Google Scholar]
  9. Hoyle G. W., Mercer E. H., Palmiter R. D., Brinster R. L. Expression of NGF in sympathetic neurons leads to excessive axon outgrowth from ganglia but decreased terminal innervation within tissues. Neuron. 1993 Jun;10(6):1019–1034. doi: 10.1016/0896-6273(93)90051-r. [DOI] [PubMed] [Google Scholar]
  10. Kapur R. P., Yost C., Palmiter R. D. A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice. Development. 1992 Sep;116(1):167–175. doi: 10.1242/dev.116.Supplement.167. [DOI] [PubMed] [Google Scholar]
  11. Kessler J. A., Ludlam W. H., Freidin M. M., Hall D. H., Michaelson M. D., Spray D. C., Dougherty M., Batter D. K. Cytokine-induced programmed death of cultured sympathetic neurons. Neuron. 1993 Dec;11(6):1123–1132. doi: 10.1016/0896-6273(93)90225-g. [DOI] [PubMed] [Google Scholar]
  12. Landis S. C. Target regulation of neurotransmitter phenotype. Trends Neurosci. 1990 Aug;13(8):344–350. doi: 10.1016/0166-2236(90)90147-3. [DOI] [PubMed] [Google Scholar]
  13. Mains R. E., Patterson P. H. Primary cultures of dissociated sympathetic neurons. I. Establishment of long-term growth in culture and studies of differentiated properties. J Cell Biol. 1973 Nov;59(2 Pt 1):329–345. doi: 10.1083/jcb.59.2.329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Metcalf D., Gearing D. P. Fatal syndrome in mice engrafted with cells producing high levels of the leukemia inhibitory factor. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5948–5952. doi: 10.1073/pnas.86.15.5948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Peuler J. D., Johnson G. A. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci. 1977 Sep 1;21(5):625–636. doi: 10.1016/0024-3205(77)90070-4. [DOI] [PubMed] [Google Scholar]
  16. Rao M. S., Patterson P. H., Landis S. C. Multiple cholinergic differentiation factors are present in footpad extracts: comparison with known cholinergic factors. Development. 1992 Nov;116(3):731–744. doi: 10.1242/dev.116.3.731. [DOI] [PubMed] [Google Scholar]
  17. Rao M. S., Sun Y., Escary J. L., Perreau J., Tresser S., Patterson P. H., Zigmond R. E., Brulet P., Landis S. C. Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons. Neuron. 1993 Dec;11(6):1175–1185. doi: 10.1016/0896-6273(93)90229-k. [DOI] [PubMed] [Google Scholar]
  18. Rao M. S., Sun Y., Vaidyanathan U., Landis S. C., Zigmond R. E. Regulation of substance P is similar to that of vasoactive intestinal peptide after axotomy or explantation of the rat superior cervical ganglion. J Neurobiol. 1993 May;24(5):571–580. doi: 10.1002/neu.480240504. [DOI] [PubMed] [Google Scholar]
  19. Raynaud B., Clarous D., Vidal S., Ferrand C., Weber M. J. Comparison of the effects of elevated K+ ions and muscle-conditioned medium on the neurotransmitter phenotype of cultured sympathetic neurons. Dev Biol. 1987 Jun;121(2):548–558. doi: 10.1016/0012-1606(87)90190-4. [DOI] [PubMed] [Google Scholar]
  20. Shadiack A. M., Hart R. P., Carlson C. D., Jonakait G. M. Interleukin-1 induces substance P in sympathetic ganglia through the induction of leukemia inhibitory factor (LIF). J Neurosci. 1993 Jun;13(6):2601–2609. doi: 10.1523/JNEUROSCI.13-06-02601.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Teitelman G., Lee J. K. Cell lineage analysis of pancreatic islet development: glucagon and insulin cells arise from catecholaminergic precursors present in the pancreatic duct. Dev Biol. 1987 Jun;121(2):454–466. doi: 10.1016/0012-1606(87)90182-5. [DOI] [PubMed] [Google Scholar]
  22. Walicke P. A., Campenot R. B., Patterson P. H. Determination of transmitter function by neuronal activity. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5767–5771. doi: 10.1073/pnas.74.12.5767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Yamamori T., Fukada K., Aebersold R., Korsching S., Fann M. J., Patterson P. H. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science. 1989 Dec 15;246(4936):1412–1416. doi: 10.1126/science.2512641. [DOI] [PubMed] [Google Scholar]
  24. Zigmond R. E., Hyatt-Sachs H., Baldwin C., Qu X. M., Sun Y., McKeon T. W., Schreiber R. C., Vaidyanathan U. Phenotypic plasticity in adult sympathetic neurons: changes in neuropeptide expression in organ culture. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1507–1511. doi: 10.1073/pnas.89.4.1507. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES