SGER: The Initiation of Mammalian Puberty: Transcriptional Regulation by POU-Domain Genes

毫无疑问，一个人一生中最有意义的事件之一就是青春期的获得。多年来，人们一直致力于解开这一发展阶段背后的神经内分泌机制。由于控制青春期的神经内分泌机制极其复杂，到目前为止，进展一直很缓慢。然而，很明显，下丘脑-垂体-性腺轴是这一过程的解剖和功能核心。此外，青春期不是一个孤立的事件造成的，而是在发育早期就开始的一系列相互依赖的过程的结果。在这个框架内，启动事件被认为发生在大脑中，在那里它们导致分泌黄体生成素释放激素(LHRH)的神经元同步激活。虽然青春期的发生和发展依赖于LHRH的产生和分泌增加，但人们对激活这一事件的分子和细胞事件知之甚少。奥杰达博士是试图解决这个错综复杂的问题的为数不多的科学家之一。有了这一小笔探索性研究拨款(SGER)，他将定义在大脑内控制青春期启动事件的基因层次。Ojeda博士将研究同源框基因的POU结构域家族是否是控制与LHRH神经网络青春期激活相关的神经元功能的基因层次的“上游”组成部分。这些基因可能是候选基因，因为它们在胚胎下丘脑中大量表达，这是LHRH神经元主要定位的大脑区域。此外，一些基因的表达在出生后发育甚至成年后的LHRH区域持续存在。Ojeda博士将使用一个实验模型，在该模型中，下丘脑损伤被用来加速未成熟女性的青春期。这一结果不仅将极大地影响我们对哺乳动物青春期的理解，还将为探索调控基因在神经系统中发挥的基础作用开辟新的途径。

There is very little doubt that one of the most meaningful events in the life span of an individual is the acquisition of puberty. Over the years, extensive efforts have been devoted to unravel the neuroendocrine mechanisms underlying this stage of development. Because the neuroendocrine mechanisms involved in the control of puberty are exceedingly complex, progress, to date, has been slow. It is clear, however, that the hypothalamic-pituitary-gonadal axis is the anatomical and functional core of the process. Moreover, puberty does not result from an isolated event, but is rather the consequence of a cascade of interdependent processes initiated very early in development. Within this framework, the initiating events are thought to occur in the brain, where they result in the synchronous activation of neurons that secrete luteinizing hormone-releasing hormone (LHRH). Although the onset and progression of puberty depends upon the increased production and secretion of LHRH, little is known about the molecular and cellular events that activate this event. Dr. Ojeda is one of the few scientists attempting to tackle this intricate and perplexing problem. With this Small Grant for Exploratory Research (SGER), he will define the gene hierarchy controlling within the brain the events underlying the initiation of puberty. Dr. Ojeda will examine whether the POU-domain family of homeobox genes are "upstream" components of the hierarchy of genes controlling neuronal functions relevant to the pubertal activation of the LHRH neuronal network. The genes are likely candidates because they are abundantly expressed in the embryonic hypothalamus, the brain region where LHRH neurons are primarily localized. Moreover, the expression of some of the genes persist in this LHRH region during post-natal development and even in adulthood. Dr. Ojeda will use an experimental model in which hypothalamic lesions are used to accelerate puberty in immature females. The results will not only impact greatly on our understanding of mammalian puberty but would open new avenues for exploring the fundamental role that regulatory genes play in the nervous system.