Development of the primary olfactory pathway

描述（由申请人提供）：本项目的长期目标是确定参与建立初级嗅觉通路复杂拓扑结构的轴突导向分子。我们以前确定了一些关键的时间点在发展中，轴突的行为表明，指导分子的作用。嗅感觉神经元（OSN）轴突在胚胎发育早期从嗅板生长到端脑泡。轴突穿过端脑，形成假定的嗅觉神经层（pONL）。一部分轴突生长到脑室表面，通过刺激细胞周期动力学，诱导嗅球（OB）的形成。大多数轴突仍然局限于pONL长达4天，大概分类成类似的子集。4天后，一些轴突生长到OB更深处，开始肾小球形成。在肾小球形成之前，OB中存在哪些阻止轴突生长的信号？ONL中存在什么样的信号阻止轴突之间的树突生长？是否存在启动单个肾小球的先驱轴突？先驱轴突或轴突群是否利用发育中OB的线索在肾小球诱导前将自己定位在适当的位置？回答这些关键问题的一种方法是检查候选指导分子在发育途径中的分布。我们推测pONL内轴突的停滞可能是由于发育中的OB内的抑制性引导分子。这种抑制性信号的一个来源可能是细胞外基质（ECM）的成分。我们已经研究了四种ECM分子的表达模式，腱生蛋白，层粘连蛋白，串珠素和硫酸软骨素蛋白聚糖（CSPGs）。其中，腱生蛋白家族的成员似乎是调节轴突生长和肾小球形成的抑制性信号的特别好的候选者。本申请的具体目的是：1）鉴定在肾小球形成期间在发育中的OB中表达的腱生蛋白家族的成员;和2）功能性地测试这些分子在体外抑制OSN神经突生长的能力。这些研究将大大提高我们对轴突如何在嗅觉系统中建立连接的认识，并可能对卡尔曼综合征等疾病产生影响。

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.