The role of an olfactory-specific histone variant in olfactory development

描述(申请人提供)：哺乳动物嗅觉感觉神经元必须从数百个基因组中“选择”表达一个化学感受器基因。除了确定神经元对气味(或信息素)的反应外，所选择的受体在细胞的生命周期中扮演着几个关键的角色。受体的活动参与控制轴突在大脑中的位置，精炼轴突投射，并控制神经元的存活时间。嗅觉神经元之间不同的神经元寿命被认为有助于改善神经元连接，消除受损神经元，并可能使动物对气味和信息素敏感。初步研究发现了一种小鼠组蛋白变异基因，其表达仅在嗅觉神经元中检测到，其表达模式与神经元活动呈负相关。组蛋白是一种与DNA直接接触的碱性蛋白质，在基因表达调控中起着关键作用。从基因组中消除嗅觉特异的组蛋白基因会导致小鼠随着年龄的增长表现出异常的体重增加和嗅觉受体基因表达的显著缺陷。对观察到的受体基因表达缺陷有两种可能的解释：1)组蛋白参与选择和/或维持受体基因的表达，或2)组蛋白参与控制神经元的寿命。这些假说将在AIMS 1和AIMS 2中得到验证。嗅觉组蛋白基因在轴突指导或细化中发挥作用的假说是从观察中产生的，因为它从基因组中消除会导致参与轴突指导的基因表达缺陷，未成熟神经元的细胞死亡率更高，以及成年人的轴突投射缺陷。组蛋白在活性依赖轴突引导或细化中的可能作用将在目标3中进行研究。分子、组织学、遗传学和高分辨率成像技术将用于完成拟议的目标。这项拟议的研究有望为神经元活动和表观遗传学如何影响外周嗅觉系统的发育、完善和可塑性提供新的机制视角，并可能对神经系统的其他部分产生重要影响。受体基因表达的选择、轴突投射的引导和完善以及神经元寿命的控制等机制问题是嗅觉系统发展和功能的核心，仍然具有特别大的挑战性。了解这些过程将对人类的嗅觉功能障碍和相关的健康问题产生重大影响。 与公共健康相关：嗅觉特异组蛋白变体在哺乳动物神经元寿命和轴突引导的活动依赖控制中的作用人类嗅觉系统包含数百种不同类型的感觉神经元，其相对丰度和与大脑的功能连接由一些知之甚少的过程控制，但这些过程对正常的嗅觉功能至关重要。我们在小鼠身上发现了一种仅在嗅觉组织中表达的基因，我们怀疑该基因可能在这些过程中发挥重要作用。对该基因的研究可能对人类的嗅觉功能障碍有重要的影响，包括与年龄相关的嗅觉衰退和与嗅觉相关的饮食障碍。

DESCRIPTION (provided by applicant): Mammalian olfactory sensory neurons must "choose" to express a single chemoreceptor gene from among hundreds in the genome. In addition to determining the odors (or pheromones) to which a neuron responds, the chosen receptor plays several critical roles during the life cycle of the cell. Activity of the receptor participates in controlling the position within the brain to which the axon is guided, refining axonal projections, and controlling how long the neuron will live. Variable neuronal longevity among olfactory neurons is thought to facilitate refinement of neuronal connections, elimination of damaged neurons, and, possibly, sensitization of an animal to odors and pheromones. Preliminary studies have led to the discovery of a mouse histone variant gene whose expression is detected only in olfactory sensory neurons in a pattern that is inversely related to neuronal activity. Histones are basic proteins that make direct contact with DNA and play critical roles in regulating gene expression. Elimination of the olfactory-specific histone gene from the genome caused mice to exhibit abnormal weight gain and significant defects in olfactory receptor gene expression as they aged. Two possible explanations for the observed defects in receptor gene expression are: 1) that the histone participates in choosing and/or maintaining receptor gene expression, or 2) that the histone participates in controlling neuronal longevity. These hypotheses will be tested in Aims 1 and 2. A hypothesis that the olfactory histone gene plays a role in axon guidance or refinement was born from observations that its elimination from the genome caused defects in the expression of genes involved in axon guidance, higher rates of cell death among immature neurons, and axonal projection defects in adults. A possible role for the histone in activity-dependent axon guidance or refinement will be investigated in Aim 3. Molecular, histological, genetic, and high-resolution imaging techniques will be used to complete the proposed aims. The proposed studies are anticipated to provide new mechanistic perspectives on how neuronal activity and epigenetics affect the development, refinement, and plasticity of the peripheral olfactory system, and may have important implications for other parts of the nervous system as well. Mechanistic issues regarding the choice of receptor gene expression, the guidance and refinement of axonal projections, and the control of neuronal longevity are central to the development and function of the olfactory system and remain particularly challenging. Understanding these processes will have major implications for olfactory dysfunction and related health problems in humans. PUBLIC HEALTH RELEVANCE: The role of an olfactory-specific histone variant in the activity-dependent control of neuronal longevity and axon guidance in mammals The human olfactory system contains hundreds of different types of sensory neurons, whose relative abundance and functional connection to the brain are controlled by processes that are poorly understood, but are critical to normal olfactory function. We have discovered a gene in mouse that is expressed only in olfactory tissues and that we suspect may play an important role in these processes. The study of this gene may have important implications for olfactory dysfunction in humans, including age-related olfactory decline and olfactory-related eating disorders.