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的数百个基因中“选择”表达单个化学受体基因。除了决定神经元对气味（或信息素）的反应外，所选择的受体在细胞的生命周期中起着几个关键作用。受体的活动参与控制大脑中轴突被引导到的位置，精炼轴突的投射，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完善，受损神经元的消除，以及动物对气味和信息素的敏感性。初步研究已经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检测到，其模式与神经元活动呈负相关。组蛋白是与DNA直接接触的基本蛋白，在调节基因表达中起着关键作用。从基因组中去除嗅觉特异性组蛋白基因会导致小鼠在衰老过程中出现异常的体重增加和嗅觉受体基因表达的显著缺陷。对于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和目标2中进行检验。嗅觉组蛋白基因在轴突引导或完善中起作用的假设来自于观察，该基因从基因组中去除会导致轴突引导相关基因的表达缺陷、未成熟神经元中较高的细胞死亡率和成人轴突投射缺陷。组蛋白在活动依赖性轴突引导或改进中的可能作用将在Aim 3中进行研究。分子、组织学、遗传和高分辨率成像技术将用于完成提出的目标。这些研究预计将为神经元活动和表观遗传学如何影响周围嗅觉系统的发育、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也有重要意义。关于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育和功能的核心，并且仍然具有特别的挑战性。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。

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.