Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.

Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes.

Demonstration of estrogen receptor α protein in glutamatergic (vesicular glutamate transporter 2 immunoreactive) neurons of the female rat hypothalamus and amygdala using double-label immunocytochemistry.

By means of double-label immunocytochemistry, authors studied the presence of estrogen receptor α (ER-α) protein in vesicular glutamate transporter 2 (VGluT2) protein-immunoreactive neurons in the female rat hypothalamus and amygdala. They examined colocalization of the 2 immunoreactive proteins in structures in which they found a significant overlap in the localization of the distribution of ER-α- and VGluT2-immunopositive nerve cells, namely in the medial preoptic area, the ventral subdivision of the ventromedial hypothalamic nucleus, and the medial amygdaloid nucleus. In the medial preoptic area, only 2.74 % of ER-α-immunoreactive neurons were VGluT2 positive, and conversely, 5 % of VGluT2-immunoreactive neurons contained ER-α immunofluorescent labeling. Highest degree of colocalization was detected in the ventral subdivision of the ventromedial hypothalamic nucleus, where 22.81 % of the ER-α-immunopositive neurons were VGluT2 immunoreactive and 37.14 % of the VGluT2-immunolabeled neurons contained ER-α-positive nucleus. In the medial amygdaloid nucleus, 15.38 % of the ER-α and 18.1 % of the VGluT2-immunoreactive neurons were double labeled. The colocalizations suggest that glutamatergic (VGluT2 protein immunoreactive) neurons are involved in the mediation of the action of estrogen on the rat brain.