GnRH Receptor Gene Expression in the Developing Rat Hippocampus: Transcriptional Regulation and Potential Roles in Neuronal Plasticity

Abstract

In the pituitary of mammals, the GnRH receptor (GnRHR) plays a primary role in the control of reproductive function. It is further expressed in the hippocampus, where its function, however, is not well defined. By quantitative RT-PCR analyses, we demonstrate herein that the onset of GnRHR gene (Gnrhr) expression in the rat hippocampus was unexpectedly delayed as compared to the pituitary and only occurred after birth. Using a previously described transgenic mouse model bearing the human placental alkaline phosphatase reporter gene under the control of the rat Gnrhr promoter, we established a positive correlation between the temporal pattern of Gnrhr mRNA levels and promoter activity in the hippocampal formation. The gradual appearance of human placental alkaline phosphatase transgene expression occurred simultaneously in the hippocampus and interconnected structures such as the lateral septum and the amygdala, coinciding with the establishment of hippocampo-septal projections. Analysis of transcription factors together with transient transfection assays in hippocampal neurons indicated that the combinatorial code governing the hippocampus-specific expression of the Gnrhr is distinct from the pituitary, likely involving transactivating factors such as NUR77, cyclic AMP response element binding protein, and Finkel-Biskis-Jinkins murine osteosarcoma virus oncogene homolog. A silencing transcription factor acting via the -3255/-1135 promoter region of the Gnrhr may be responsible for the transcriptional repression observed around birth. Finally, GnRH directly stimulated via activation of its receptor the expression of several marker genes of neuronal plasticity such as Egr1, synaptophysin, and spinophilin in hippocampal primary cultures, suggesting a role for GnRHR in neuronal plasticity. Further characterization of these mechanisms may help unravel important functions of GnRH/GnRHR signaling in the brain.

Transcriptional regulation of brain gene expression in response to a territorial intrusion

“…This finding strongly suggests the involvement of transcription regulatory networks in response to an intruder. This is consistent with studies that have shown that the production of GnRH and its receptors is under the control of a 'transcription code' involving IEGs [51] and supports the hypothesis that POMC and GnRH-controlled neurons modulate behaviour via transcription regulatory networks operating within and across brain regions.…”

Rat Gnrhr promoter directs species-specific gene expression in the pituitary and testes of transgenic mice

“…8B). This marked difference in mouse and rat promoter activities in the testis is reminiscent of our previous observations in the hippocampus where similar divergence between those two promoter activities was identified (Schang et al 2011b). In both cases, the rat transgenic promoter displays the same behaviour during embryonic and postnatal development as the rat endogenous Gnrhr, despite the mouse context.…”

“…Within the promoters of these species, several response elements and related transcription factors involved in the gonadotrope-specific and regulated expression of pituitary Gnrhr have been identified (Pincas et al 1998, Jorgensen et al 2004, Hapgood et al 2005, Granger et al 2006, Schang et al 2013a. Studies of these promoters in the ovary, placenta and hippocampus indicate that Gnrhr expression is driven by the same promoter with, however, different response elements and sets of transcription factors (Kang et al 2000, Cheng et al 2002, Schang et al 2011b, 2013b.…”

Identification and Analysis of Two Novel Sites of Rat GnRH Receptor Gene Promoter Activity: The Pineal Gland and Retina

“…This indicates that a unique promoter is able to direct Gnrhr expression in multiple and nevertheless specific brain areas [10]. Recently, we have extended the analysis of Gnrhr expression to embryonic and postnatal developmental stages in extrapituitary sites, notably including the limbic system, in order to improve our knowledge about the temporal onset and time course of Gnrhr promoter activity [11,12]. In these studies, the rat promoter directed Gnrhr-hPLAP transgene expression according to a rat species-specific pattern despite the mouse context, especially in the limbic system [11] as well as in the pituitary after castration [manuscript in preparation].…”

“…Recently, we have extended the analysis of Gnrhr expression to embryonic and postnatal developmental stages in extrapituitary sites, notably including the limbic system, in order to improve our knowledge about the temporal onset and time course of Gnrhr promoter activity [11,12]. In these studies, the rat promoter directed Gnrhr-hPLAP transgene expression according to a rat species-specific pattern despite the mouse context, especially in the limbic system [11] as well as in the pituitary after castration [manuscript in preparation]. This observation is in agreement with a study using mice carrying human chromosome 21 showing that, in homologous tissues, genetic sequence is largely responsible for directing species-specific transcription whereas other interspecies differences, namely cellular environment, play secondary roles [13].…”