Migration of early olfactory neuronal progenitors

描述(申请人提供)：促性腺激素释放激素(GnRH，又称LHRH)的分泌对调节脑下垂体-性腺轴和确保几乎所有脊椎动物的生殖能力至关重要。在胚胎和出生后早期发育过程中，促性腺激素释放激素神经元从嗅觉平台穿过筛板和嗅球，迁移到前脑和下丘脑。这些神经元的迁移路径由起源于穹隆鼻器(VNO)的轴突组成，并从嗅球直接投射到前脑吻侧。初步研究表明，SDF-1/CXCR4信号在促性腺激素释放激素神经元迁移中起关键作用。在CXCR4-/-小鼠中，几乎没有GnRH神经元到达腹侧前脑。这些小鼠可能是Kallmann综合征(KS)或特发性低促性腺激素减退(IHH)的理想模型。我们将分析SDF-1/CXCR4在小鼠体内和体外研究中的作用，并试图确定KS或IHH患者是否存在SDF-1或CXCR4基因突变。我们还将分析Kisspeptin/Gpr54信号在影响GnRH神经元亚群的迁移率和移动方向方面的作用。这些实验是为了平衡使用正常和突变小鼠进行的体内研究与测试特定途径或机制的体外研究。补充方法对于确保我们的结果将与GnRH神经元系统的基本生物学相关是重要的。在体内，我们将使用几个突变小鼠品系来分析它们在GnRH神经元迁移中的作用。在体外，我们将测试不同的信号是否通过相同或相似的机制驱动GnRH神经元移动/迁移。我们将使用来自转基因动物的体外切片培养，通过视频显微镜测试单个GnRH神经元的机制，在转基因动物中，绿色荧光蛋白(GFP)在GnRH神经元中选择性表达。这些研究将有助于理解引导GnRH神经元到达其在下丘脑的适当目的地以控制下丘脑-垂体-性腺轴的复杂因素。

DESCRIPTION (provided by applicant): The secretion of Gonadotropin-releasing hormone (GnRH, also called LHRH) is critical for regulating the pituitary-gonadal axis and ensuring reproductive competence for virtually all vertebrates. GnRH neurons migrate from the olfactory placode across the cribriform plate and olfactory bulb, into the forebrain and hypothalamus during embryonic and early postnatal development. The migratory pathway for these neurons consists of axons that originate in the vomeronasal organ (VNO), and project beyond the olfactory bulb directly into the rostral forebrain. Preliminary studies show that SDF-1/CXCR4 signaling plays a critical role in GnRH neuron migration. Virtually no GnRH neurons reach the ventral forbrain in CXCR4-/- mice. These mice may represent an ideal model for Kallmann Syndrome (KS) or Idiopathic Hypogonadotropic Hypogonadism (IHH). We will analyze the role of SDF-1/CXCR4 in vivo and in vitro studies in mouse and will seek to determine whether individuals with KS or IHH may have SDF-1 or CXCR4 gene mutations. We will also analyze the role of kisspeptin/GPR54 signaling for their ability to influence the mobility and direction of movement of subsets of GnRH neurons. These experiments are proposed to balance studies in vivo using normal and mutant mice with studies in vitro that test particular pathways or mechanisms. The complementary approach is important for ensuring that our results will be relevant to the basic biology of the GnRH neuronal system. In vivo, we will use several lines of mutant mice to analyze their roles in migration of GnRH neurons. In vitro, we will test whether different cues signal through the same or similar mechanisms to drive GnRH neuron movement/migration. We will test mechanisms in individual GnRH neurons by video microscopy using in vitro slice cultures derived from transgenic animals in which green fluorescent protein (GFP) is selectively expressed in GnRH neurons. These studies will lead to an understanding of the complex factors that guide GnRH neurons to their proper destinations in the hypothalamus to control the hypothalamic-pituitary-gonadal axis.