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

描述（由申请人提供）：哺乳动物嗅觉感觉神经元必须从基因组中的数百个基因中“选择”表达单个化学感受器基因。除了决定神经元所响应的气味（或信息素）之外，所选择的受体在细胞的生命周期中起着几个关键作用。受体的活动参与控制轴突在大脑中的位置，改善轴突投射，并控制神经元的寿命。嗅觉神经元之间的可变神经元寿命被认为有助于神经元连接的细化，消除受损的神经元，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，其表达仅在嗅觉感觉神经元中以与神经元活动呈负相关的模式检测到。组蛋白是与DNA直接接触的碱性蛋白质，在调节基因表达中起关键作用。从基因组中删除嗅觉特异性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着缺陷。对于所观察到的受体基因表达缺陷的两种可能的解释是：1）组蛋白参与选择和/或维持受体基因表达，或2）组蛋白参与控制神经元寿命。这些假设将在目标1和2中得到检验。嗅觉组蛋白基因在轴突导向或细化中发挥作用的假说是从观察中产生的，即从基因组中消除嗅觉组蛋白基因会导致参与轴突导向的基因表达缺陷，未成熟神经元中细胞死亡率较高，以及成年人的轴突投射缺陷。组蛋白在活性依赖性轴突引导或细化中的可能作用将在目标3中研究。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。 这些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。关于受体基因表达的选择、轴突投射的指导和细化以及神经元寿命的控制的机制问题是嗅觉系统的发展和功能的核心，并且仍然特别具有挑战性。了解这些过程将对人类嗅觉功能障碍和相关健康问题产生重大影响。 公共卫生相关性：嗅觉特异性组蛋白变异体在哺乳动物神经元寿命和轴突导向的活性依赖性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知之甚少的过程控制，但对正常的嗅觉功能至关重要。我们在小鼠中发现了一个只在嗅觉组织中表达的基因，我们怀疑它可能在这些过程中起重要作用。对该基因的研究可能对人类嗅觉功能障碍具有重要意义，包括与年龄相关的嗅觉衰退和与嗅觉相关的饮食失调。

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.