携带Dax1突变的病人常表现出下丘脑和垂体缺陷，并多发神经内分泌疾病--特发性低促性腺激素性性腺功能减退症（简称IHH症）。在人及模式动物胚胎发育中，Dax1蛋白在下丘脑中表达，但当前对Dax1在下丘脑发育中的作用及其生理功能尚无研究报导。由于在Dax1突变小鼠中没有出现促性腺激素表达异常等现象，限制了对Dax1突变导致IHH症的发病机制的研究，也阻碍了对Dax1在下丘脑中功能作用的认识。项目预实验发现斑马鱼Dax1突变可导致下丘脑发育异常,同时伴有促性腺激素表达失调，以及生殖能力显著下降等现象。这些结果提示在斑马鱼模式动物中可较好地模拟Dax1突变导致的IHH症，而下丘脑中神经元发育异常可能是导致疾病的关键因素。项目研究将深入考察Dax1在斑马鱼下丘脑神经元发育中的作用机制及其生理功能，从而促进对相关疾病的发病机制的理解，并为Dax1突变导致IHH症的对症治疗提供线索。

Human patients with Dax1 mutations often have hypothalamus-pituitary defects, and many patients may manifest idiopathic hypogonadotropic hypogonadism (IHH) upon adolescence. Dax1 is expressed in the hypothalamic tissues in both human and other vertebrate model animals. However, the functions, mechanisms and likely physiological roles of Dax1 in hypothalamus development are currently unknown. Because the mouse Dax1 knockout model lacks gonadotropic defects, it hasn’t been investigated if and how Dax1 functions in hypothalamus, and as a consequence the cause of hypogonadism in human Dax1 patients is not well understood. We disrupted the Dax1 gene in the zebrafish and discovered the mutant animals have hypothalamus defects, accompanied by abnormal expression of gonadotropins and reduced fecundity. These results indicate the zebrafish Dax1 model mimics human Dax1 mutations’ effects, and suggest the hypothalamic defect may be a primary cause in the IHH. This research proposal will examine in detail the functions, mechanisms, and physiological roles of Dax1 in hypothalamus development. The proposed studies should provide insight into the mechanisms of disease, and bring about new clues for the cures of the hypogonadotropic hypogonadism caused by the Dax1 mutations.