A Role for Migrating Olfactory Placode Cells in Olfactory Nerve Development

描述(由申请人提供)：公共卫生相关性：神经发育事件的中断是导致一系列疾病的原因，包括自闭症、脆性X、利脑畸形和卡尔曼综合症，这些疾病严重影响我们的社会。作为一个医学界，在我们能够弄清楚如何治疗这些脱落性疾病之前，我们必须首先在分子和细胞水平上了解哪些事件在发育过程中出了问题。这项研究探索了嗅觉通路的形成作为一个模型系统，以指导我们对分子和细胞发育中的关键原理的理解，包括轴突引导、细胞迁移和细胞分化。只有深入了解这些基本过程，我们才能在治疗神经发育障碍方面取得进展。具体地说，这项建议侧重于初级嗅神经通路(ONP)的发展，该通路将位于OE中的嗅觉神经元(OSNs)连接到嗅球(OB)。ONP的形成由一系列协调事件组成，包括嗅觉定位(OP)内细胞的分化，嗅觉神经元(OSN)轴突向间充质的延伸，最后轴突向可能的嗅球(POB)靠近。我们的目标是了解这一通路的正确形成和发育中的嗅神经通路(ONP)内轴突的组织所必需的初始关键事件。早期的研究发现，间充质内的神经元样细胞与OSN轴突关系密切。我们的工作假设是这些是OP来源的前驱神经元，我们称之为迁移性嗅觉定位细胞(MOPC)，它们在建立OE和OB之间的初始地形时，为OSN轴突提供了一个支架或框架。具体地说，我们假设在ONP的形成及其接近POB的过程中，MOPC作为OSN轴突的底物。这一假说基于以下几点：首先，在整个中枢神经系统中，有证据表明导向柱神经元影响轴突路径的形成。第二，我们的初步数据表明，OSN轴突在最初的MOPC向间充质转变后从OP中出现。第三，一些MOPC表达气味受体(ORs)，这与OSN轴突引导有关[1]。这些数据表明，MOPC的定位不是随机的，而是发生在分子定义的地形上，这是嗅神经和OSN轴突靶向形成的基础。我们的首要目标是描述MOPC的特征以及它们在建立嗅觉上皮和POB之间的接口中可能扮演的角色(S)。

DESCRIPTION (provided by applicant): Public health relevance: Disruptions in neurodevelopmental events are responsible for a wide range of diseases, including Autism, Fragile X, Lissencephaly, and Kallman's syndrome, that severely affect our society. Before we, as a medical community, can figure out how to treat these devestating disorders, we must first understand on a molecular and cellular level what events have gone wrong developmentally. This study explores the formation of the olfactory pathway as a model system to guide our understanding of critical principles in molecular and cellular development, including axon guidance, cell migration, and cellular differentiation. Only by gaining insight into these fundamental processes will we be able to make progress towards the treatment of neurodevelopmental disorders. Specifically, this proposal focuses on the development of the primary olfactory nerve pathway (ONP), which connects the olfactory sensory neurons (OSNs), which reside in the OE, to the olfactory bulb (OB). The formation of the ONP is comprised of a series of coordinated events that includes the differentiation of cells within the olfactory placode (OP), extension of olfactory sensory neuron (OSN) axons into the mesenchyme, and finally the approach of the axons to the presumptive olfactory bulb (pOB). Our goal is to understand the initial key events central to the proper formation of this pathway and the organization of the axons within the developing olfactory nerve pathway (ONP). Earlier studies noted neuron-like cells within the mesenchyme in close apposition to the OSN axons. Our working hypothesis is that these are OP derived pioneer neurons, which we have termed migrating olfactory placode cells (MOPCs), that contribute to a scaffold or framework utilized by the OSN axons as they establish the initial topography between the OE and OB. Specifically, we hypothesize that MOPCs act as a substrate for the OSN axons during the formation of the ONP and its approach to the pOB. This hypothesis is based on the following: First, throughout the CNS there is evidence for guidepost neurons infiuencing the formation of axon pathways. Second, our preliminary data demonstrate that OSN axons emerge from the OP after the initial transition of MOPCs into the mesenchyme. Third, some MOPCs express odor receptors (ORs) which have been implicated in OSN axon guidance (1). These data suggest that the positioning of the MOPCs is not stochastic but, rather, occurs within a molecularly defined topography that underlies the formation of the olfactory nerve and OSN axon targeting. Our overarching goal is a characterization of the MOPCs and the role(s) they may play in establishing the interface between the olfactory epithelium and pOB.