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

定义 SEMA3E 和 PLXND1 在调节哺乳动物有性生殖的 GnRH 神经元系统中的作用

• 批准号: BB/L002639/1
• 负责人: Christiana Ruhrberg
• 金额: $ 48.94万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL002639%2F1
• 关键词: Defining; role; SEMA3E; PLXND1; GnRH

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.

在胎儿发育期间，促性腺激素释放激素（GnRH）神经元在鼻子中诞生，必须迁移到下丘脑，下丘脑是大脑的一个结构，这些神经元与血管接触，将它们产生的激素分泌到全身循环中。在GnRH神经元系统的建立过程中出现的错误会损害激素分泌，从而延迟青春期和有性生殖，例如Kallmann综合征。因此，了解GnRH神经元系统是如何形成的，为了解遗传疾病（如Kallmann综合征）的起源提供了重要的信息，并有助于在寻求基因诊断和治疗的患者中确定突变筛查的新靶点。例如，早期诊断导致GnRH神经元缺乏的遗传缺陷，可以及时使用激素治疗来改善或预防症状的发生。然而，到目前为止，只有一些遗传原因被确定。最近，我们发现了一种叫做VEGF-A的信号分子，当GnRH神经元通过鼻子迁移到大脑时，可以促进它们的存活。我们还发现，一种名为SEMA3A的不同信号分子对于建立迁移GnRH神经元到达大脑的神经“高速公路”至关重要。我们的发现支持了其他人随后的研究，他们发现了损害Kallmann综合征患者SEMA3A功能的基因突变。我们现在正在寻求资金来研究GnRH神经元系统中相关的信号蛋白SEMA3E及其受体PLXND1，因为我们的前期实验表明，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。这项研究将显著增强我们对GnRH神经元系统的理解，并为寻求生殖疾病遗传诊断的患者推进新测试的发展。

项目成果

HS6ST1 insufficiency causes self-limited delayed puberty in contrast with other GnRH deficiency genes

与其他 GnRH 缺乏基因相比，HS6ST1 不足会导致自限性青春期延迟

• DOI: 10.1530/ey.16.7.4
• 发表时间: 2019
• 期刊: Yearbook of Paediatric Endocrinology
• 作者: SR H

HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes.

与其他 GnRH 缺乏基因相比，HS6ST1 不足会导致自限性青春期延迟。

• DOI: 10.1210/jc.2018-00646
• 发表时间: 2018-09-01
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Howard SR;Oleari R;Poliandri A;Chantzara V;Fantin A;Ruiz-Babot G;Metherell LA;Cabrera CP;Barnes MR;Wehkalampi K;Guasti L;Ruhrberg C;Cariboni A;Dunkel L
• 通讯作者: Dunkel L