Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0674, USA.
Center for Circadian Biology, University of California, San Diego, La Jolla, CA, 92093, USA.
Mol Neurobiol. 2018 Nov;55(11):8709-8727. doi: 10.1007/s12035-018-1013-0. Epub 2018 Mar 27.
Mating behavior in males and females is dependent on olfactory cues processed through both the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Signaling through the MOE is critical for the initiation of male mating behavior, and the loss of MOE signaling severely compromises this comportment. Here, we demonstrate that dosage of the homeodomain gene Six3 affects the degree of development of MOE but not the VNO. Anomalous MOE development in Six3 heterozygote mice leads to hyposmia, specifically disrupting male mounting behavior by impairing detection of volatile female estrus pheromones. Six3 is highly expressed in the MOE, main olfactory bulb (MOB), and hypothalamus; all regions essential in the proper migration of the gonadotropin-releasing hormone (GnRH) neurons, a key reproductive neuronal population that migrates along olfactory axons from the developing nose into the brain. Interestingly, we find that the reduction in Six3 expression in Six3 heterozygote mice compromises development of the MOE and MOB, resulting in mis-migration of GnRH neurons due to improper olfactory axon targeting. This reduction in the hypothalamic GnRH neuron population, by 45% in adulthood, leads to female subfertility, but does not impact male hormone levels, suggesting that male infertility is not related to GnRH neuron numbers, but exclusively linked to abnormal olfaction. We here determine that Six3 is haploinsufficient for MOE development, GnRH neuron migration, and fertility, and represents a novel candidate gene for Kallmann syndrome, a form of inherited infertility.
雌雄两性的交配行为依赖于通过主嗅觉上皮 (MOE) 和犁鼻器 (VNO) 处理的嗅觉线索。MOE 的信号传导对于启动雄性交配行为至关重要，而 MOE 信号的丧失严重损害了这种行为。在这里，我们证明同源域基因 Six3 的剂量会影响 MOE 的发育程度，但不会影响 VNO。Six3 杂合子小鼠异常的 MOE 发育导致嗅觉减退，特别是通过损害对挥发性雌性发情信息素的检测来破坏雄性交配行为。Six3 在 MOE、主嗅觉球 (MOB) 和下丘脑高度表达；所有这些区域对于促性腺激素释放激素 (GnRH) 神经元的正确迁移至关重要，GnRH 神经元是一种关键的生殖神经元群体，沿着嗅觉轴从发育中的鼻子迁移到大脑。有趣的是，我们发现 Six3 杂合子小鼠中 Six3 表达的减少会损害 MOE 和 MOB 的发育，导致 GnRH 神经元的迁移异常，因为嗅觉轴突的靶向不当。成年后，下丘脑 GnRH 神经元群体减少了 45%，导致雌性生育能力下降，但不影响雄性激素水平，这表明男性不育与 GnRH 神经元数量无关，而仅与嗅觉异常有关。我们在这里确定 Six3 对于 MOE 发育、GnRH 神经元迁移和生育能力是半合子不足的，并且代表了 Kallmann 综合征（一种遗传性不育症）的一个新候选基因。
