Defining the role of SEMA3E and PLXND1 in the GnRH neuron system that regulates sexual reproduction in mammals

在胎儿发育过程中，促性腺激素释放激素(GnRH)神经元在鼻子中出生，必须迁移到下丘脑，在下丘脑中，这些神经元与血管接触，将它们产生的激素分泌到大循环中。在建立促性腺激素释放激素神经系统的过程中所犯的错误会损害激素的分泌，从而延迟青春期和有性生殖，例如在Kallmann综合征的情况下。因此，了解GnRH神经元系统是如何形成的，对于了解Kallmann综合征等遗传性疾病的起源提供了重要的内幕信息，并有助于确定寻求基因诊断和治疗的患者进行突变筛查的新靶点。例如，对导致促性腺激素释放激素神经元缺陷的遗传缺陷的早期诊断可以及时用激素治疗来改善或防止症状的出现。然而，到目前为止，只有部分遗传原因被确定。最近，我们发现一种名为VEGF-A的信号分子在GnRH神经元通过鼻子迁移到大脑时促进它们的存活。我们还发现，一种名为SEMA3A的不同信号分子对于建立神经“高速公路”至关重要，迁移的GnRH神经元在这条高速公路上旅行到达大脑。我们的发现支持了随后对其他人的研究，他们发现了损害Kallmann综合征患者SEMA3A功能的基因突变。我们现在寻求资金来研究GnRH神经元系统中被称为SEMA3E及其受体PLXND1的相关信号素，因为我们的初步实验表明，这两个分子的相互作用在GnRH神经元发育的后期阶段是必不可少的。这项研究将显著提高我们对GnRH神经元系统的了解，并推动为寻求生殖障碍基因诊断的患者开发新的测试方法。

During foetal development, gonadotropin releasing hormone (GnRH) neurons are born in the nose and must migrate to the hypothalamus, a brain structure in which these neurons make contact with blood vessels to secrete the hormone they produce into the general circulation. Mistakes made during the establishment of the GnRH neuron system impair hormone secretion and therefore delay puberty and sexual reproduction, for example in the condition Kallmann Syndrome. Accordingly, understanding how the GnRH neuron system forms provides important inside into the origin of genetic disorders such as Kallmann Syndrome and help identify novel targets for mutation screening in patients seeking genetic diagnosis and treatment. For example, the early diagnosis of genetic defects that cause GnRH neuron deficiency allows timely treatment with hormone therapy to ameliorate or prevent the onset of symptoms. However, only some of the genetic causes have been identified so far. Recently, we discovered that a signalling molecule called VEGF-A promotes the survival of GnRH neurons when they migrate through the nose to reach the brain. We also discovered that a different signalling molecule called SEMA3A is essential to establish the neural 'highway' on which migrating GnRH neurons travel to reach the brain. Our findings underpinned subsequent studies of others, who identified genetic mutations that impair SEMA3A function in patients with Kallmann Syndrome. We now seek funding to study a related semaphorin known as SEMA3E and its receptor PLXND1 in the GnRH neuron system, because our pilot experiments suggest that the interaction of these two molecules is essential at later stages of GnRH neuron development. This research will significantly enhance our understanding of the GnRH neuron system and advance the development of novel tests for patients seeking genetic diagnosis for reproductive disorders.