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Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor

Nature Neuroscience volume 11, pages 285–291 (2008)Cite this article

Abstract

The extracellular calcium-sensing receptor (CaSR) monitors the systemic, extracellular, free ionized-calcium level ([Ca2+]o) in organs involved in systemic [Ca2+]o homeostasis. However, CaSR is also expressed in the nervous system, where its role is unknown. We found large amounts of CaSR in perinatal mouse sympathetic neurons when their axons were innervating and branching extensively in their targets. Manipulating CaSR function in these neurons by varying [Ca2+]o, using CaSR agonists and antagonists, or expressing a dominant-negative CaSR markedly affected neurite growth in vitro. Sympathetic neurons lacking CaSR had smaller neurite arbors in vitro, and sympathetic innervation density was reduced in CaSR-deficient mice in vivo. Hippocampal pyramidal neurons, which also express CaSR, had smaller dendrites when transfected with dominant-negative CaSR in postnatal organotypic cultures. Our findings reveal a crucial role for CaSR in regulating the growth of neural processes in the peripheral and central nervous systems.

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Figure 1: CaSR expression in the developing SCG.
Figure 2: [Ca2+]o influences neurite growth from SCG neurons at the peak of CaSR expression.
Figure 3: Developmental time course of effects of [Ca2+]o on neurite growth from SCG neurons.
Figure 4: CaSR calcimimetic and calcilytic compounds enhance and inhibit the effects of [Ca2+]o on neurite growth from E18 SCG neurons, respectively.
Figure 5: DNCaSR and wild-type CaSR have opposing effects on neurite growth from cultured SCG neurons.
Figure 6: Deletion of Casr reduces sympathetic axon growth in vitro and in vivo.
Figure 7: DNCaSR impairs the growth of postnatal hippocampal pyramidal dendrites.

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Acknowledgements

We thank D. Shoback and W. Chang for the antibody to CaSR carboxy terminus, and NPS Pharmaceuticals for the gift of NPS R-467 and of NPS 89636. We thank G. Lloyd for use of the radiometer 125. This work was supported by grants from the Wellcome Trust and Biotechnology and Biological Sciences Research Council. T.NV. was a recipient of a studentship from the Biotechnology and Biological Sciences Research Council.

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Authors and Affiliations

  1. School of Biosciences, Biomedical Building, Museum Avenue, Cardiff, CF10 3US, UK

    Thomas N Vizard, Gerard W O'Keeffe, Humberto Gutierrez, Daniela Riccardi & Alun M Davies

  2. Vitamins & Carcinogenesis Laboratory, HNRCA at Tufts University, Boston, 02111, Massachusetts, USA

    Claudine H Kos

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Contributions

T.N.V. and G.W.O. conducted the experiments on sympathetic neurons, H.G. conducted the experiments on hippocampal neurons, C.H.K. generated the CaSR mutant mice, and D.R. and A.M.D. supervised the project.

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Correspondence to Daniela Riccardi or Alun M Davies.

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Vizard, T., O'Keeffe, G., Gutierrez, H. et al. Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nat Neurosci 11, 285–291 (2008). https://doi.org/10.1038/nn2044

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