Development of the primary olfactory pathway

初级嗅觉通路的发育

• 批准号: 6649560
• 负责人: HELEN B TRELOAR
• 金额: $ 8.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649560
• 关键词: Kallmann's syndrome; chondroitin sulfates; extracellular matrix; heparan sulfate; immunocytochemistry; in situ hybridization; laboratory mouse; laminin; neuronal guidance; olfactory lobe; polymerase chain reaction; proteoglycan; sensory mechanism; tenascin; western blottings

DESCRIPTION (provided by applicant): The long term aim of this project is to identify axon guidance molecules involved in establishing the complex topography of the primary olfactory pathway. We previously identified some critical time points in development where axon behavior indicates that guidance molecules are acting. Olfactory sensory neuron (OSN) axons grow from the olfactory placode to the telencephalic vesicle in early embryonic development. Axons penetrate the telencephalon, forming a presumptive olfactory nerve layer (pONL). A subset of axons grow to the ventricular surface, which by way of stimulating cell cycle kinetics, the formation of olfactory bulb (OB) is induced. The majority of axons remain restricted to the pONL for up to 4 days, presumably sorting out into like subsets. After 4 days, some axons grow deeper into the OB, initiating glomerular formation. What are the cue(s) that are present in the OB that prevent axon in growth prior to glomerular formation? What cues are present in the ONL that prevent dendritic outgrowth amongst axons? Do pioneer axons exist that initiate individual glomeruli? Do pioneer axons or groups of axons use cues in the developing OB to position themselves in the appropriate position prior to glomerular induction? One way to answer these key questions is to examine the distributions of candidate guidance molecules within the developing pathway. We hypothesize that the stalling of axons within the pONL may be due to inhibitory guidance molecules within the developing OB. One source of such inhibitory cues may be components of the extra cellular matrix (ECM). We have examined the expression patterns of four ECM molecules, tenascin, laminin, perlecan, and chondroitin sulfate proteoglycans (CSPGs). Of these, members of the tenascin family appear particularly good candidates for the inhibitory cues that regulate axon in growth and glomerular formation. The specific aims of the current application are to: 1) identify members of the tenascin family that are expressed in the developing OB during the period of glomerular formation; and 2) to functionally test the ability of theses molecules to inhibit OSN neurite outgrowth in vitro. These studies will greatly enhance our knowledge of how axons establish connections in the olfactory system and may have implications for diseases such as Kallman's syndrome.

描述(由申请人提供)：该项目的长期目标是确定参与建立初级嗅觉通路复杂地形图的轴突引导分子。我们之前发现了发育中的一些关键时间点，轴突行为表明引导分子正在发挥作用。嗅觉神经元(OSN)轴突在胚胎发育早期从嗅觉定位区向端脑小泡生长。轴突穿透端脑，形成嗅神经层(PONL)。一部分轴突生长到脑室表面，通过刺激细胞周期动力学，诱导形成嗅球(OB)。大多数轴突停留在pONL上长达4天，推测是分类成类似的子集。4天后，一些轴突深入OB，开始形成肾小球。是什么信号(S)出现在OB中，在肾小球形成之前阻止轴突生长？ONL中有什么信号可以阻止轴突间的树突生长？是否存在启动单个肾小球的先锋轴突？在肾小球诱导之前，先锋轴突或轴突群是否使用发育中的OB中的线索来将自己定位在合适的位置？回答这些关键问题的一种方法是检查候选引导分子在发育过程中的分布。我们推测，pONL内轴突的停滞可能是由于发育中的OB内的抑制导向分子所致。这种抑制性线索的一个来源可能是细胞外基质(ECM)的成分。我们研究了四种细胞外基质分子，张力蛋白、层粘连蛋白、多聚糖和硫酸软骨素蛋白多糖(CSPGs)的表达模式。其中，Tenascin家族的成员似乎特别适合于调节轴突生长和肾小球形成的抑制信号。目前应用的具体目的是：1)鉴定在肾小球形成过程中发育的OB中表达的Tenascin家族成员；2)从功能上测试这些分子在体外抑制OSN轴突生长的能力。这些研究将极大地提高我们对轴突如何在嗅觉系统中建立联系的了解，并可能对诸如卡尔曼综合症之类的疾病产生影响。