Migration of early olfactory neuronal progenitors

描述（由申请人提供）：促性腺激素释放激素（GnRH，也称为LHRH）的分泌对于调节垂体-性腺轴和确保几乎所有脊椎动物的生殖能力至关重要。GnRH神经元在胚胎和出生后早期从嗅板穿过筛板和嗅球迁移到前脑和下丘脑。这些神经元的迁移途径由起源于犁鼻器（VNO）的轴突组成，并越过嗅球直接投射到吻侧前脑。初步研究表明，SDF-1/CXCR 4信号在GnRH神经元迁移中起着关键作用。在CXCR 4-/-小鼠中，几乎没有GnRH神经元到达腹侧前脑。这些小鼠可能是卡尔曼综合征（KS）或特发性低促性腺激素性性腺功能减退症（IHH）的理想模型。我们将在小鼠体内和体外研究中分析SDF-1/CXCR 4的作用，并试图确定KS或IHH个体是否可能有SDF-1或CXCR 4基因突变。我们还将分析kisspeptin/GPR 54信号传导影响GnRH神经元亚群的移动性和移动方向的作用。这些实验旨在平衡使用正常和突变小鼠的体内研究与测试特定途径或机制的体外研究。互补的方法是很重要的，以确保我们的结果将相关的GnRH神经元系统的基础生物学。在体内，我们将使用几种突变小鼠来分析它们在GnRH神经元迁移中的作用。在体外，我们将测试不同的线索是否通过相同或相似的机制来驱动GnRH神经元运动/迁移。我们将通过视频显微镜使用转基因动物的体外切片培养物（其中绿色荧光蛋白（GFP）选择性地在GnRH神经元中表达）来测试单个GnRH神经元中的机制。这些研究将导致对指导GnRH神经元在下丘脑中的适当目的地以控制下丘脑-垂体-性腺轴的复杂因素的理解。

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.