Development of the primary olfactory pathway

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的轴突引导分子。我们之前确定了一些关键的时间点，轴突的行为表明引导分子在起作用。嗅觉感觉神经元（OSN）轴突在胚胎早期发育过程中从嗅觉位点向端脑泡生长。轴突穿透端脑，形成假定的嗅觉神经层（pONL）。一部分轴突生长到心室表面，通过刺激细胞周期动力学，诱导形成嗅球（OB）。大多数轴突被限制在pONL长达4天，大概是被分类成类似的子集。4天后，一些轴突深入OB，开始肾小球形成。在肾小球形成之前，OB中有哪些因素阻止轴突生长？在ONL中存在什么线索阻止轴突之间的树突生长？是否存在启动单个肾小球的先锋轴突？先锋轴突或轴突群是否利用OB发育中的线索在肾小球诱导前将自己定位到适当的位置？回答这些关键问题的一种方法是检查候选指导分子在发展途径中的分布。我们假设pONL内轴突的停滞可能是由于OB发育中的抑制性引导分子。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ECM分子的表达模式，tenascin，层粘连蛋白，perlecan和硫酸软骨素蛋白聚糖（CSPGs）。其中，tenascin家族的成员似乎是调节轴突生长和肾小球形成的抑制线索的特别好的候选者。当前应用的具体目的是：1)确定在肾小球形成期间发展中的OB中表达的tenascin家族成员；2)在体外功能测试这些分子抑制OSN神经突生长的能力。这些研究将极大地增强我们对轴突如何在嗅觉系统中建立连接的认识，并可能对诸如卡尔曼综合征之类的疾病产生影响。

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.