A Role for Migrating Olfactory Placode Cells in Olfactory Nerve Development

嗅基板细胞迁移在嗅神经发育中的作用

• 批准号: 7751429
• 负责人: ALEXANDRA MILLER
• 金额: $ 4.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751429
• 关键词: Adult; Affect; Afferent Neurons; Age; Autistic Disorder; Axon; Biological Models; Cell Differentiation process; Cells; Characteristics; Communities; Data; Development; Disease; Embryo; Event; Fragile X Syndrome; Goals; Lateral; Medial; Medical; Mesenchyme; Messenger RNA; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Odors; Olfactory Epithelium; Olfactory Nerve; Olfactory Pathways; Pathway interactions; Play; Population; Population Distributions; Positioning Attribute; Process; Reporting; Role; Series; Site; Societies; Specificity; Syndrome; System; Testing; Time; Vesicle; Work; axon guidance; base; cell motility; cellular development; insight; lissencephaly; malformation; migration; molecular phenotype; olfactory bulb; public health relevance; receptor; scaffold; segregation

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.

描述（由申请人提供）： 公共健康相关性：神经发育事件的中断会导致多种疾病，包括自闭症、脆性 X 肌瘤、无脑畸形和卡尔曼综合症，这些疾病严重影响我们的社会。作为医学界，在我们弄清楚如何治疗这些毁灭性的疾病之前，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作为模型系统的形成，以指导我们理解分子和细胞发育的关键原理，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，我们才能在神经发育障碍的治疗方面取得进展。具体来说，该提案重点关注初级嗅觉神经通路（ONP）的发展，该通路将位于 OE 中的嗅觉感觉神经元（OSN）连接到嗅球（OB）。 ONP 的形成由一系列协调事件组成，包括嗅基板 (OP) 内细胞的分化、嗅觉感觉神经元 (OSN) 轴突向间充质的延伸，以及最终轴突接近假定嗅球 (pOB)。我们的目标是了解对于该通路的正确形成以及发育中的嗅神经通路（ONP）内轴突的组织至关重要的初始关键事件。早期研究注意到间充质内的神经元样细胞与 OSN 轴突紧密相连。我们的工作假设是，这些是 OP 衍生的先驱神经元，我们将其称为迁移嗅板细胞 (MOPC)，它们有助于 OSN 轴突在建立 OE 和 OB 之间的初始拓扑时使用的支架或框架。具体来说，我们假设 MOPC 在 ONP 形成及其接近 pOB 的过程中充当 OSN 轴突的基质。该假设基于以下基础：首先，在整个中枢神经系统中，有证据表明路标神经元影响轴突通路的形成。其次，我们的初步数据表明，在 MOPC 最初转变为间充质后，OSN 轴突从 OP 中出现。第三，一些 MOPC 表达与 OSN 轴突引导有关的气味受体 (OR) (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拓扑内，该拓扑是嗅觉神经和 OSN 轴突靶向形成的基础。我们的首要目标是表征 MOPC 以及它们在建立嗅觉上皮和 pOB 之间的界面中可能发挥的作用。