Rabconnectin-3\u03b1 is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness

Brooke K Tata,Stéphane Peineau,Nicolas De Roux,Zsolt Csaba,Carole Harbulot,Sandrine Jacquier

doi:10.1038/srep42463

Abstract

A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show that brain expression levels of Dmxl2, which encodes the vesicular protein rabconnectin-3α, determine the capacity of GnRH neurons to be activated by kisspeptin and estradiol. We also demonstrate that Dmxl2 expression levels control the pruning of GnRH dendrites, highlighting an unexpected role for a vesicular protein in the maturation of GnRH neuronal network. This effect is mediated by rabconnectin-3α in neurons or glial cells afferent to GnRH neurons. The widespread expression of Dmxl2 in several brain areas raises the intriguing hypothesis that rabconnectin-3α could be involved in the maturation of other neuronal populations.

Highlights

We previously found that rbcn-3αis expressed in the organum vasculosum of the lamina terminalis (OVLT) and in the median eminence (ME)[9], where GnRH neurons undergo extensive dendritic morphogenesis during the juvenile period of rodent life[15]
We observed a decrease of GnRH-ir neurons in mice in which Dmxl[2] was deleted solely in GnRH neurons, the reproductive phenotype observed was mild and did not yield the functional defect as to which we observed in nes::cre;Dmxl2wt/loxp mice
These results reveal the critical role of the expression level of rbcn-3αin the brain for the post-natal homeostasis of the GnRH neuronal network

Summary

Introduction

We previously found that rbcn-3αis expressed in the organum vasculosum of the lamina terminalis (OVLT) and in the median eminence (ME)[9], where GnRH neurons undergo extensive dendritic morphogenesis during the juvenile period of rodent life[15]. We previously reported that nes::cre;Dmxl2wt/loxp mice display a 30% loss of GnRH-immunoreactive neurons[9]. As such defect cannot fully explain the reproductive deficit observed in these mice, we suspected that an additional functional alteration might affect the GnRH neuronal network of nes::cre;Dmxl2wt/loxp mice. As the use of the cre recombinase under the control of the nestin promoter results in the deletion of the critical exon in neuronal progenitors[17], we sought to clarify whether low expression of rbcn3-αin neurons or glial cells may disturb the maturation and the activation of GnRH neurons, and what is the underlying mechanism leading to the reproductive deficit in these mice. As rbcn3-αis ubiquitously expressed in the brain and its function is vital after birth, we propose that the characterization of rbcn3-αfunction in the GnRH neuronal network will bring new insights on the understanding of neuronal maturation

Methods

Results

Conclusion