突触细胞粘附分子Necl2与女性青春期发育的生物学功能研究

Connection and transmission of messages between synapses in hypothalamus is essential for the initiation of puberty development. As a synaptic cell adhesive molecular, Necl2 plays an important role in the interactions between neurons and glial cells. Previous studies revealed that Necl2 involves in the regulation of female mouse sexual maturation. .Idiopathic hypogonadotrophic hypogonadism (IHH) is one of the reasons of female delayed puberty maturation which is not received enough attention so far. In this project, it is expected that amino acids mutation leading to IHH could be found at the molecular level by screening female IHH patients with Necl2 exon sequences in peripheral blood; It would be verified whether Necl2 affects GnRH releasing by hypothalamic neurons and whether it is caused by abnormal cell adhesions at the cellular level; By using in situ hybridization, we found that Necl2 was prominently expressed in the ventromedial hypothalamic nucleus(VMH). The VMH nucleus plays an important role in female sexual development and maturation. Therefore the Necl2-knockout mice that we have gotten will give more solid evidences about how the gene impacts the morphology and position of VMH and the behavior of female sexual development. Our research will use the molecular, cellular and animal modes to reveal the concrete mechanism that Necl2 participates in the regulation of female puberty development in hypothalamus and is one of the reasons that causes IHH.

下丘脑突触间的信息传递对于青春期启动发挥重要作用。Necl2是一种突触细胞粘附分子，与神经元与胶质细胞之间的信息传递有关，前期研究发现Necl2参与调控雌性小鼠性成熟过程。女性特发性低促性腺激素性性腺功能低减（IHH）是引起女性青春期发育延迟的重要原因，但未得到足够重视。本研究通过筛查女性IHH患者外周血中Necl2外显子序列，从分子水平发现引起女性青春期发育延迟的异常氨基酸关键位点；从细胞水平验证Necl2是否对下丘脑神经元释放GnRH功能产生影响，并验证这种改变是否是由于细胞粘附异常引起；预实验检测到Necl2表达于小鼠下丘脑的腹内侧核，而腹内侧核在雌性性行为方面发挥重要作用，构建Necl2敲除小鼠可以进一步研究该基因对腹内侧核团形态和位置的影响及小鼠行为学变化。本研究通过分子、细胞和在体动物不同水平，证明Necl2参与下丘脑影响女性青春期发育的调控过程，是造成女性IHH的原因之一。