Submitted on August 10, 2005
Accepted on September 6, 2006
Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: Potential impact on reduced GnRH neuron population in CaR-null mice
Naibedya Chattopadhyay1*, Kyeong-Hoon Jeong2, Shozo Yano3, Su Huang1, Jian L Pang1, Xianghui Ren1, Ernest Terwilliger1, Ursula B Kaiser3, Peter M. Vassilev4, Martin R. Pollak3, and Edward M. Brown1
1 Medicine, Brigham and Womens Hospitaland Harvard Medical School, Boston, Massachusetts, United States; Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine, Bsoton, Massachusetts, United States
2 Medicine, Brigham and WOmen's Hospital, Boston, Massachusetts, United States
3 Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
4 Endocrine-Hypertension Division, Dept. of Medicine, Brigham&Women's Hospital and Harvard medical School, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: naibedya{at}rics.bwh.harvard.edu.
The factors controlling the migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CaR) promotes chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus-derived) and GN11 (olfactory bulb-derived). Elevated extracellular Ca2+ concentrations promoted chemotaxis of both cell types, with a greater effect in GN11 cells. This effect was CaR-mediated, as in both cell types overexpression of a dominant negative CaR attenuated high Ca2+-stimulated chemotaxis. We also demonstrated expression of a 
-chemokine, monocyte chemoattractant protein-1 (MCP-1) and its receptor, CC motif receptor 2 (CCR2), in the hypothalamic GnRH neurons, as well as in GT1-7 and GN11 cells. Exogenous MCP-1 stimulated chemotaxis of both cell lines and the effect was greater in GN11 than in GT1-7 cells, consistent with the higher CCR2 mRNA levels in GN11 cells. Activating the CaR stimulated MCP-1 secretion in GT1-7 but not in GN11 cells. MCP-1 secreted in response to CaR stimulation is biologically active, as conditioned medium from GT1-7 cells treated with high Ca2+ promoted chemotaxis of GN11 cells, and this effect was partially attenuated by a neutralizing antibody to MCP-1. Finally, the number of GnRH neurons in the basal fore brain was ~27% lower in CaR-null mice than in mice expressing the CaR gene. We conclude that the CaR may be a novel regulator of GnRH neuronal migration likely involving, in part, MCP-1.
