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Title: Determining a role for the calcium-sensing receptor (CaR) in neuronal development
Author: Vizard, Thomas N.
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2006
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The calcium-sensing receptor (CaR) is expressed in neurons of the adult central and peripheral nervous systems (PNS). There are currently no data describing the expression or function of the CaR during neuronal development. CaR mRNA expression was detected in sympathetic and sensory mouse ganglia at a number of embryonic (E) and postnatal (P) ages where, in superior cervical ganglia (SCG), CaR mRNA expression peaked at El8. At this age CaR protein was localised to the cell soma of dissociated neurons and throughout the neurite field. When compared to neurons grown in low (0.7mM) extracellular Ca2+ concentration (Ca2+ 0), high (2.3mM) Ca 2+ 0 increased SCG neurite outgrowth within a specific developmental window, E18-P0, correlating with a time when these neurons are exposed to a systemic Ca 0 of 1.7mM in vivo. SCG neurite outgrowth within this window was susceptible to pharmacological modulation of the CaR by calcimimetic and calcilytic compounds, increasing and decreasing neurite growth, respectively. Expression of a dominant negative CaR (R185Q) reduced outgrowth of El8 neurite arbors, whereas overexpression of a wild-type CaR re-introduced Ca 0 sensitivity of neurons outside the developmental window. Consistent with these data, Car' SCG neurons displayed impaired neurite arborisation in vitro and sympathetic target innervation in vivo when compared to Car+/ and Car+/+ neurons. This role for the CaR is not limited to the PNS. Overexpression of the dominant negative CaR in P4 hippocampus reduced neurite outgrowth of CA2 and CA3 pyramidal neurons. Preliminary data also suggest a role for the CaR in neuronal survival, where increasing Ca2+ 0 from 0.7 to 2.3mM increased El8 SCG survival in a dose-dependent manner. Further, high Ca 0 enhances NGF-dependent survival, an effect that can be reduced using the calcilytic compound. These data are the first to show that Ca 0 modulates neurite growth and neuronal survival during development and that these effects of Ca2+ 0 are mediated though the CaR.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available