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1 March 2006 Expression of a Dominant Negative FGF Receptor in Developing GNRH1 Neurons Disrupts Axon Outgrowth and Targeting to the Median Eminence
John C. Gill, Pei-San Tsai
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Abstract

During development, neurons that synthesize and release gonadotropin-releasing hormone (GNRH1) extend their axons to the median eminence (ME) to establish neurosecretory contacts necessary for hormone secretion. Signals that coordinate this process are not known, but could involve the activation of fibroblast growth factor receptors (FGFRs) expressed on developing GNRH1 neurons. Using both whole-animal and cell culture approaches, this study examines the direct role of FGFR signaling in the extension and guidance of GNRH1 axons to the ME. In vivo retrograde labeling with fluorogold (FG) first showed a significant reduction in the projections of GNRH1 axons to the circumventricular organs (including the ME) in transgenic mice expressing a dominant negative FGF receptor (dnFGFR) in GNRH1 neurons. Using a primary GNRH1 neuronal culture system, we examined if compromised axon extension and directional growth led to the reduced axon targeting efficiency seen in vivo. Primary cultures of GNRH1 neurons were established from Embryonic Day 15.5 embryos, an age when GNRH1 neurons are actively targeting the ME. Cultured GNRH1 neurons expressing dnFGFR (dnFGFR neurons) exhibited attenuated activation of signaling pathways and reduced neurite outgrowth in response to FGF2. Further, dnFGFR neurons failed to preferentially target neurites toward cocultured ME explant and FGF2-coated beads, suggesting a defect in axon pathfinding. Together, these findings describe a direct role of FGFR signaling in the elongation and guidance of GNRH1 axons to the ME.

John C. Gill and Pei-San Tsai "Expression of a Dominant Negative FGF Receptor in Developing GNRH1 Neurons Disrupts Axon Outgrowth and Targeting to the Median Eminence," Biology of Reproduction 74(3), 463-472, (1 March 2006). https://doi.org/10.1095/biolreprod.105.046904
Received: 31 August 2005; Accepted: 1 November 2005; Published: 1 March 2006
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