Neuregulin-β induces expression of an NMDA-receptor subunit

Abstract

Neuregulins (also known as ARIA, NDF, heregulin, GGF) are a family of widely expressed growth and differentiation factors. Neuregulins secreted from motor neurons accumulate at maturing neuromuscular junctions, where they stimulate transcription of genes encoding specific acetylcholine receptors. How these factors function at central synapses, however, is unknown. In the maturing cerebellum, neuregulins are concentrated in glutamatergic mossy fibres that innervate granule cells in the internal granule-cell layer1. We have analysed the effects of neuregulins on the expression of genes encoding NMDA (N-methyl-D-aspartate) receptors in the cerebellum, because receptor composition changes dramatically as expression of the receptor NR2C subunit is specifically induced in neurons in the internal granule-cell layer during synaptogenesis. Here we report that addition of a neuregulin-β isoform to cultured cerebellar slices specifically increases the expression of NR2C messenger RNAs by at least 100-fold; effects are only minor with a neuregulin-α isoform. This stimulation of NR2C expression requires synaptic activity by NMDA receptors, as well as neuregulin-β. Addition of the NMDA-receptor-channel blocker AP-5 prevents upregulation of the NR2C subunit by neuregulin, whereas an AMPA/kainate-receptor antagonist does not. Consistent with these effects of neuregulin, we find that granule cells express its receptors ErbB2 and ErbB4 before the NR2C subunit of the NMDA receptor. Our results indicate that neuregulins regulate the composition of neurotransmitter receptors in maturing synapses in the brain, in a manner analogous to the neuromuscular junction.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Cerebellar granule cells migrate in slice cultures and gross slice morphology is unaffected by neuregulin.
Figure 2: Neuregulin-β selectively stimulates expression of the NR2C gene.
Figure 3: Neuregulin EGF-domain-containing peptides are unable to stimulate NR2C expression.
Figure 4: Neuregulin receptor mRNAs and proteins are expressed in cerebellar granule cells.
Figure 5: Neuregulin-dependent NR2C expression requires neuronal activity.

References

  1. 1

    Sandrock, A. J., Goodearl, A. D., Yin, Q. W., Chang, D. & Fischbach, G. D. ARIA is concentrated in nerve terminals at neuromuscular junctions and at other synapses. J. Neurosci. 15, 6124–6136 (1995).

    CAS  Article  Google Scholar 

  2. 2

    Watanabe, M., Inoue, Y., Sakimura, K. & Mishina, M. Developmental changes in distribution of NMDA receptor channel subunit mRNAs. NeuroReport 3, 1138–1140 (1992).

    CAS  Article  Google Scholar 

  3. 3

    Farrant, M., Feldmeyer, D., Takahashi, T. & Cull-Candy, S. NMDA-receptor channel diversity in the developing cerebellum Nature 368, 335–339 (1994).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Feldmeyer, D. & Cull-Candy, S. Functional consequences of changes in NMDA receptor subunit expression during development. J. Neurocytol. 25, 857–867 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Stern, P., Behe, P., Schoepfer, R. & Colquhoun, D. Single-channel conductances of NMDA receptors expressed from cloned cDNAs: comparison with native receptors. Proc. R. Soc. Lond. B. 250, 271–277 (1992).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Takahashi, T. et al. Functional correlation of NMDA receptor epsilon subunits expression with the properties of single-channel and synaptic currents in the developing cerebellum. J. Neurosci. 16, 4376–4382 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Kadotani, H. et al. Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J. Neurosci. 16, 7859–7867 (1996).

    CAS  Article  Google Scholar 

  8. 8

    Akazawa, C., Shigemoto, R., Bessho, Y., Nakanishi, S. & Mizuno, N. Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J. Comp. Neurol. 347, 150–160 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Buonanno, A. & Sasner, M. Gradients of NMDA receptor expression in developing cerebellar granule cells. Soc. Neurosci. Abstr. 21, 398.5 (1995).

    Google Scholar 

  10. 10

    Tanaka, M., Tomita, A., Yoshida, S., Yano, M. & Shimizu, H. Observation of the highly organized development of granule cells in rat cerebellar organotypic cultures. Brain Res. 641, 319–327 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Audinat, E., Lambolez, B., Rossier, J. & Crepel, F. Activity-dependent regulation of N-methyl-D-aspartate receptor subunit expression in rat cerebellar granule cells. Eur. J. Neurosci. 6, 1792–1800 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Fischbach, G. & Rosen, K. ARIA: A neuromuscular junction neuregulin. Annu. Rev. Neurosci. 20, 429–458 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Sandrock, A. J. et al. Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276, 599–603 (1997).

    Article  Google Scholar 

  14. 14

    Meyer, D. & Birchmeier, C. Distinct isoforms of neuregulin are expressed in mesenchymal and neuronal cells during mouse development. Proc. Natl Acad. Sci. USA 91, 1064–1068 (1994).

    ADS  CAS  Article  Google Scholar 

  15. 15

    Lu, H. S. et al. Studies on the structure and function of glycosylated and nonglycosylated neu differentiation factors. Similarities and differences of the alpha and beta isoforms. J. Biol. Chem. 270, 4784–4791 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Dong, Z. et al. Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 15, 585–596 (1995).

    CAS  Article  Google Scholar 

  17. 17

    Jo, S. A., Zhu, X., Marchionni, M. A. & Burden, S. J. Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature 373, 158–161 (1995).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Chu, G. C., Moscoso, L. M., Sliwkowski, M. X. & Merlie, J. P. Regulation of the acetylcholine receptor epsilon subunit gene by recombinant ARIA: an in vitro model for transynaptic gene regulation. Neuron 14, 329–339 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Altiok, N., Bessereau, J. L. & Changeux, J. P. ErbB3 and ErbB2/neu mediate the effect of heregulin on acetylcholine receptor gene expression in muscle: differential expression at the endplate. EMBO J. 14, 4258–4266 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Lu, H. S. et al. Post-translational processing of membrane-associated neu differentiation factor proisoforms expressed in mammalian cells. J. Biol. Chem. 270, 4775–4783 (1995).

    CAS  Article  Google Scholar 

  21. 21

    Peles, E. & Yarden, Y. Neu and its ligands: From an oncogene to neural factors. BioEssays 15, 815–824 (1993).

    CAS  Article  Google Scholar 

  22. 22

    Lemke, G. Neuregulins in development. Mol. Cell. Neurosci. 7, 247–262 (1996).

    CAS  Article  Google Scholar 

  23. 23

    Carraway, K. L. & Cantley, L. C. Aneu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell 78, 5–8 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Moscoso, L. M. et al. Synapse-associated expression of an acetylcholine receptor-inducing protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle. Dev. Biol. 172, 158–169 (1995).

    CAS  Article  Google Scholar 

  25. 25

    Levi, G., Gordon, R. D., Gallo, V., Wilkin, G. P. & Balazs, R. Putative acidic amino acid transmitters in the cerebellum. I. Depolarization-induced release. Brain Res. 239, 425–445 (1982).

    CAS  Article  Google Scholar 

  26. 26

    Mishina, M. et al. Molecular distinction between fetal and adult forms of muscle acteylcholine receptor. Nature 321, 406–411 (1986).

    ADS  CAS  Article  Google Scholar 

  27. 27

    Komuro, H. & Rakic, P. Modulation of neuronal migration by NMDA receptors. Science 260, 95–97 (1993).

    ADS  CAS  Article  Google Scholar 

  28. 28

    Shahar, A., de Vellis, J., Vernadakis, A. & Haber, B. A Dissection and Tissue Culture Manual of the Nervous System(Liss, New York, (1989)).

    Google Scholar 

  29. 29

    Carroll, S. L., Miller, M. L., Frohnert, P. W., Kim, S. S. & Corbett, J. A. Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J. Neurosci. 17, 1642–1659 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Angerer, L. M. & Angerer, R. C. Detection of poly A+ RNA in sea urchin eggs and embryos by quantitative in situ hybridization. Nucleic Acids Res. 9, 2819–2840 (1981).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Z. Yang, J. Cheng and Y. Miyazaki for technical assistance, S. Carroll for erbB cDNAs, Z. Hall and P. Nelson for critically reading the manuscript, and NICHD for support.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Andres Buonanno.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ozaki, M., Sasner, M., Yano, R. et al. Neuregulin-β induces expression of an NMDA-receptor subunit. Nature 390, 691–694 (1997). https://doi.org/10.1038/37795

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.