Regulation of Temporal and Spatial Organization of Newborn GnRH Neurons by IGF Signaling

新生神经元如何在正确的时间组织到正确的位置以形成功能回路是发育神经生物学中的一个基本问题。一个有吸引力的模型系统，以解决这个问题是促性腺激素释放激素（GnRH）神经元系统。GnRH神经元是生殖系统的主要调节者。它们分泌GnRH肽来启动生殖活动。GnRH神经元的异常发育可导致生殖障碍。虽然在理解GnRH神经元在生殖中的核心重要性方面已经取得了重大进展，但对GnRH祖细胞（即，未分化的）细胞位于发育中的神经系统中，以及它们如何被指示成为GnRH神经元。这个项目填补了我们知识的空白。预期的结果将提供关于胰岛素样生长因子（IGF）信号传导（一种主要的胚胎生长促进途径）如何调节GnRH神经元发育的新知识。从该项目中获得的知识可能在水产养殖业中有应用，并将有助于了解生殖障碍的病因。该项目为高中生、本科生、研究生和博士后研究员提供培训机会。学生参与这个前沿研究项目的各个方面。与密歇根大学自然历史博物馆合作，该项目还包括开发一个神经生物学夏令营课程，题为“大脑中闪亮的神经元！”对于K-12学生。这项活动和其他外联活动使这项由国家科学基金会资助的研究向公众开放。一个有吸引力的模型系统，以解决新生神经元如何组织到正确的位置与正确的时机，以形成功能电路的问题是GnRH神经元系统。GnRH神经元出现在早期胚胎的鼻/嗅基板，并进行长距离迁移，从嗅觉区的视前区和下丘脑。GnRH祖细胞的胚胎起源仍有争议。关于这些祖细胞是如何被指定产生GnRH神经元的，我们知之甚少。大多数脊椎动物物种有第二个GnRH基因，在中脑表达。关于GnRH 2神经元的发育和调节知之甚少。该项目测试的假设，这两种类型的GnRH神经元起源于颅神经嵴和/或光学基板衍生的祖细胞和IGF信号调节GnRH神经元的出现在正确的时间和位置通过控制增殖，迁移和/或其祖细胞的存活。在胚胎发育早期的关键时间窗口中，IGF信号的扰动改变了新生GnRH神经元的时空组织，这反过来又影响了以后的生殖功能。目的1探讨胚胎起源的GnRH神经元;目的2确定是否IGF信号调节的GnRH神经元的出现，通过控制迁移，增殖和/或生存的祖细胞，和目的3确定这种调节的长期生殖后果。

How newborn neurons are organized into the right locations with the right timing to form functional circuits is a fundamental question in developmental neurobiology. An attractive model system in which to address this question is the Gonadotropin-releasing hormone (GnRH) neuronal system. GnRH neurons are master regulators of the reproductive system. They secrete GnRH peptides to initiate reproductive activity. Abnormal development of GnRH neurons can lead to reproductive disorders. Although significant advances have been made in understanding the central importance of GnRH neurons in reproduction, very little is known about where the GnRH progenitor (i.e., undifferentiated) cells are located in the developing nervous system and how they are instructed to become GnRH neurons. This project fills this gap in our knowledge. The anticipated results will provide new knowledge on how insulin-like growth factor (IGF) signaling, a major embryonic growth-promoting pathway, regulates GnRH neuronal development. The knowledge gained from this project may have applications in the aquaculture industry and will help understand the etiology of reproductive disorders. This project provides training opportunities for high school, undergraduate, and graduate students, and postdoctoral fellows. The students participate in all aspects of this cutting-edge research project. In collaboration with the University of Michigan Museum of Natural History, the project also includes the development of a summer camp curriculum in neurobiology, entitled "Shining Neurons in the Brain!", for K-12 students. This and other outreach activities make this NSF-funded research accessible to the public. An attractive model system in which to address the question of how newborn neurons are organized into the right locations with the right timing to form functional circuits is the GnRH neuronal system. GnRH neurons emerge from the nasal/olfactory placode in early embryos and undertake a long-distance migration from the olfactory region to the preoptic area and hypothalamus. The embryonic origin(s) of GnRH progenitor cells is still under debate. Little is known about how these progenitor cells are specified to give rise to GnRH neurons. Most vertebrate species have a second GnRH gene that is expressed in the midbrain. Much less is known about the GnRH2 neuron development and regulation. This project tests the hypothesis that the two types of GnRH neurons originate from the cranial neural crest- and/or optical placode-derived progenitor cells and that IGF signaling regulates the emergence of GnRH neurons at the right time and location by controlling the proliferation, migration, and/or survival of their progenitor cells. Perturbation of IGF signaling in a critical time window during early embryogenesis alters the temporal and spatial organization of the newborn GnRH neurons, which, in turn, affects reproductive function later in life. Aim 1 investigates the embryonic origins of GnRH neurons; Aim 2 determines whether IGF signaling regulates the emergence of the GnRH neurons by controlling migration, proliferation, and/or survival of their progenitor cells, and Aim 3 determines the long-term reproductive consequences of this regulation.