FP04-2 Rabconnectin-3α: A Synaptic Protein That Is a Key Regulator of the Gonadotropic Axis in Humans and Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP04-GnRH & Gonadotroph Biology & Signaling
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:05 AM
Room 135 (Moscone Center)

Poster Board SAT-137
Brooke Kaigler Tata*1, Juliane Leger2, Lukas Hujibregts1, Sandrine Jacquier1, Jean-Claude Carel3 and Nicolas de Roux1
1Hospital Robert Debre, Paris, France, 2Hosp Robert Debre, Paris, France, 3Paediatric Endocrinology, Hosp Robert Debre, Paris, France
Recently, the neuroendocrine network regulating GnRH secretion during puberty (i.e. Kisspeptin (KP) and Neurokinin B) has become better understood. However, the molecular mechanisms modulating the plasticity of this neuroendocrine network are unknown. Inability of maturation of this network results in the absence of puberty and leads to isolated hypogonadotropic hypogonadism (IHH). Many mutations causing IHH have been described for genes encoding neuropeptides and their receptors. However, puberty is not limited to just a change in neuropeptide activity. Thus, we extended our research to syndromic IHH with neuronal dysfunctions to discover proteins involved in the neuroendocrine plasticity of the hypothalamus-pituitary-gonadotropic (HPG) axis. We discovered a new phenotype associating IHH, ataxia and diabetes in three brothers with a homozygous loss-of-function mutation in DMXL2. DMXL2 encodes for rabconnectin-3α (rbcn3-α), a synaptic protein interacting with regulators of Ras-associated binding-3a (Rab3a) proteins, which are involved in synaptic plasticity.

We studied the role of rbcn3-α in pubertal onset by producing Dmxl2-knock-out mice. Our results revealed no significant phenotype in heterozygous (HET) Dmxl2 hypomorphic mice, which are fertile. We hypothesized that mice with both HET hypomorphic and neuronally deleted Dmxl2 (Dmxl2/Nes-Cre) would display worsened parameters of puberty. Indeed, Dmxl2/Nes-Cre HET mice are infertile. Dmxl2/Nes-Cre HET female mice had a significant delay in puberty associated with few ovulations, confirmed by low numbers of corpus lutea. HET male Dmxl2/Nes-Cre mice had significantly shorter anogenital distance and undetectable testosterone levels. Important, we observed that rbcn3-α is co-localized with synaptophysin and vesicular glutamate transporter (VGLUT)-2 in the ME and is involved in vesicle exocytosis.

Our results reveal that rbcn3-α plays a key role in puberty in both humans and mice. These studies expose a novel mechanism in the activation of the HPG axis whereby rbcn3-α is a synaptic protein that could modulate glutamate, KP, and/or GnRH release in the ME. Rbcn3-α may be one major protein controlling the plasticity of the neuroendocrine network regulating GnRH release.  As patients with a Dmxl2 deficiency have been discovered, these data are of great clinical relevance, allowing a deeper understanding of the reactivation of the HPG axis at puberty.

Nothing to Disclose: BKT, JL, LH, SJ, JCC, ND

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Brooke K. Tata is supported by the DIM "Cerveau et Pensée" scholarship for this work.