ESPE Abstracts (2015) 84 FC-LB2

Loss of Neuronal Dmxl2 Impairs the Maturation and the Activation of GnRH Neurons: a New Mechanism of GnRH Deficiency

Carole Harbulot, Brooke Tata, Sandrine Jacquier & Nicolas De Roux

Inserm U1141, Paris Diderot University, 75019 Paris, France

Background: DMXL2 haploinsufficiency in humans was recently shown to cause the polyendocrine-polyneuropathia syndrome including a GnRH deficiency (OMIM #616113). The neuronal deletion of Dmxl2 in mice (Nes::Cre;Dmxl2loxp/wt) caused infertility and gonadotropic deficiency (Plos Biology 9 e1001952, 2014). Dmxl2 encodes rabconnectin-3α (rbcn-3α), which participates in the control of the V-ATPase activity and regulatory secretion. The association between a defect in a synaptic protein and GnRH deficiency was novel and suggested a new mechanism.

Objective and hypotheses: To characterize the mechanism of the GnRH deficiency caused by loss of neuronal Dmxl2, in mice.

Method: An extensive analysis of GnRH neuron development and activation was performed in Nes::Cre;Dmxl2-/wt mice as well as in a mouse line with a complete knock out of Dmxl2 in GnRH neurons (GnRH::Cre;Dmxl2loxp/loxp).

Results: Nes::Cre;Dmxl2loxp/wt mice exhibited 30% decrease of GnRH neurons in the hypothalamus but an increase of immature GnRH neurons as compared to WT mice. GnRH neurons did not respond to Kisspeptin stimulation in male Nes::Cre;Dmxl2loxp/wt mice and female Nes::Cre;Dmxl2loxp/wt mice did not respond to the estradiol-induced positive feedback. This defect of the GnRH maturation and activation was associated with an impaired glutamatergic signaling pathway in the hypothalamus. To delineate the role of rbcn-3α in GnRH neurons as compared to other hypothalamic neurons, we created a mouse line with a full deletion of Dmxl2 in GnRH neurons. GnRH::Cre;Dmxl2loxp/loxp male mice were subfertiles whereas GnRH::Cre;Dmxl2loxp/loxp females were infertile. These mice exhibited a similar developmental defects of the GnRH neuron morphology than in Nes::Cre;Dmxl2loxp/wt mice. GnRH::Cre;Dmxl2loxp/loxp female mice exhibited advanced vaginal opening yet the time to first estrus was delayed associated with abnormal estrous cyclicity.

Conclusion: Low neuronal expression of Dmxl2 impairs the maturation and the activation of GnRH neurons, most likely by a defect in synaptogenesis. These results open new perspectives to understand mechanisms of puberty disorders.

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