Our lab recently discovered that low expression of DMXL2 causes a new complex neurological phenotype with GnRH deficiency in humans. DMXL2 encodes rabconnectin-3α (rbcn3-α), a vesicular protein interacting with regulators of RAB3a, which is important for synaptic homeostasis. To understand the role of rbcn3-α in GnRH deficiency, we used a conditional neuronal Dmxl2 knock out (KO) mouse to understand if deletion of DMXL2 in neurons causes deleterious reproductive defects.
Indeed, Dmxl2 neuronal KO mice exhibit delayed puberty and are infertile. Female Dmxl2 neuronal KO mice exhibit normal maturation of ovarian follicles until the late antral follicle stages with significantly less corporal lutea, spending 10% of their estrous cycle in proestrus, demonstrating limited ovulation and indeed do not reproduce. Paradoxically, these females exhibit markedly higher luteinizing hormone levels, suggestive of a defective GnRH neuronal network. Lastly, Dmxl2 neuronal KO mice exhibited normal pituitary response to GnRH, as well as normal ovarian response to PMSG, further validating the defect as central.
We discovered that rbcn3-α is highly expressed in the OVLT and median eminence (ME), important areas for GnRH neuron activity. Rbcn3-α co-localizes with GnRH axonal extremities in the ME. Interestingly, adult Dmxl2 neuronal KO mice exhibit a significant decrease of GnRH mRNA associated with a loss of total GnRH neurons with the most significant loss in the OVLT. In all, these data confirm that the GnRH neuronal network is defective due to deletion of Dmxl2 in neurons.
Overall, this study demonstrates that neuronal loss of a novel vesicular protein of the HPG axis causes a loss of GnRH neurons and decreased GnRH mRNA, leading to pubertal defects and infertility. This elucidates a novel mechanism of GnRH deficiency, highlighting the indirect/direct role of the vesicular protein, rbcn3-α, in the central control of the HPG axis for the activation of puberty and fertility.