Molecular Mechanisms Controlling Differentiation and Circuit Formation of Vomeronasal Sensory Neurons

控制犁鼻感觉神经元分化和回路形成的分子机制

• 批准号: 10049241
• 负责人: Paolo E Forni
• 金额: $ 38.52万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049241
• 关键词: AVPR2 gene; Accessory Olfactory Bulbs; Affect; Afferent Neurons; Affinity; Aging; Animal Behavior; Animal Model; Animals; Apical; Area; Axon; Basement membrane; Behavior; Bioinformatics; Biological Models; Brain; Cells; Cellular Structures; Characteristics; Collagen Type IV; DNA Sequence Alteration; Data; Defect; Dementia; Detection; Disease; Ectopic Expression; Embryonic Development; Environmental Risk Factor; Epithelial; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Identity; Genetically Modified Animals; Goals; Health; Homeostasis; Human; Instinct; Kallmann Syndrome; Knockout Mice; Knowledge; Life; Longevity; Maintenance; Mental Depression; Metabolic; Metabolic Diseases; Mission; Molecular; Molecular Biology; Multiple Sclerosis; Mus; Natural regeneration; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Olfactory Epithelium; Olfactory Pathways; Olfactory dysfunction; Parkinson Disease; Patients; Pattern; Pharmaceutical Preparations; Pheromone; Population; Quality of life; Receptor Gene; Regulator Genes; Research; Rodent; Role; Schizophrenia; Signal Induction; Signal Transduction; Site; Structure; Symptoms; Testing; Therapeutic; Three-Dimensional Imaging; Tissues; United States National Institutes of Health; Vertebrates; Work; behavior test; bone morphogenic protein; cell type; chromatin immunoprecipitation; differential expression; gene induction; improved; innovation; interdisciplinary approach; loss of function; mouse genetics; mouse model; nervous system disorder; neuroepithelium; neurogenesis; next generation sequencing; novel diagnostics; novel therapeutic intervention; postnatal; programs; receptor; regenerative; selective expression; social; stem; stem cells; symptom treatment; transcription factor; transcriptome; vomeronasal organ

SUMMARY The nervous system is composed of thousands of different neuronal cell types. Neuronal identity and connectivity is defined by the expression of specific gene batteries. How neuronal identity is initiated and maintained is central to understand the molecular causes underlying neurodegenerative diseases. Olfactory dysfunctions often occur in aging, metabolic disorders, and numerous neurological disorders, including depression, Parkinson’s disease, multiple sclerosis, schizophrenia and dementia. Understanding what signals control terminal differentiation, expression patterns, plasticity, and homeostasis of olfactory neurons will fill a critical gap in knowledge. Our proposed studies will identify key mechanisms that underlie neuronal identity, axonal targeting and homeostasis of a specialized chemosensory epithelium. Our overall objective will delineate the molecular connections between olfactory deficits and neurological dysfunctions. The vomeronasal organ (VNO) is a specialized olfactory subsystem responsible to detect pheromones. While humans do not have a functional VNO, the human olfactory epithelium shares some characteristics with the VNO. As a model system, the VNO has a simple cellular structure with a small number of stem/progenitor cells that generate new sensory neurons throughout life. We chose to use this simplified model system to study mechanisms that control neurogenesis, neuron differentiation, cellular plasticity and homeostasis across postnatal life. The neuro-epithelium of the VNO is composed of two main classes of neurons that selectively express receptors encoded by two vomeronasal receptor (VR) gene families: V1R and V2R. While both neuronal types originate from a common pool of progenitor cells, V1R and V2R expressing neurons localize to different areas within the VNO and project to different areas of the accessory olfactory bulb. Our central hypothesis states that the transcription factor tfap2e (AP2e) controls basal VSN’s identity, cell composition of the VNO and its connectivity to the brain. We propose that the vomeronasal sensory neurons retain a high level of cellular plasticity that allows them to be reprogrammed even after terminal differentiation. Moreover, we propose that bone morphogenic protein BMP signaling gradients established by BMP affinity to collagen IV (5, 6), in the basement membrane, initiate the basal differentiation program, AP2e expression and maintenance of the basal VSNs genetic identity throughout life. Our innovative approach will exploit state of the art mouse genetics, 2D and 3D imaging, next generation sequencing, chromatin immunoprecipitation (Chip)-seq, bioinformatics and behavioral testing to uncover the mechanisms that define and maintain the identity of chemosensory neurons in postnatal animals. The proposed research is significant as to understand critical gene regulatory networks in a specialized chemo-sensory epithelium and how changes in morphogenic signaling in postnatal animals affect its cellular composition, tissue homeostasis and neuronal connectivity and to identify mechanisms underlying chemosensory decline and neurodegeneration in humans. The findings from our proposed studies may produce therapeutic strategies to improve the human condition. !

概括 神经系统由数千种不同的神经元细胞类型组成。神经元身份和连接 由特定基因组的表达来定义。神经元身份如何启动和维持是核心 了解神经退行性疾病的分子原因。经常出现嗅觉障碍 衰老、代谢紊乱和许多神经系统疾病，包括抑郁症、帕金森病、 多发性硬化症、精神分裂症和痴呆症。了解什么信号控制终端分化， 嗅觉神经元的表达模式、可塑性和稳态将填补知识的关键空白。我们的 拟议的研究将确定神经元身份、轴突靶向和稳态的关键机制 专门的化学感应上皮。我们的总体目标将描绘分子连接 嗅觉缺陷和神经功能障碍之间。犁鼻器（VNO）是一个专门的 嗅觉子系统负责检测信息素。虽然人类没有功能性的 VNO，但人类 嗅觉上皮与 VNO 有一些共同特征。作为一个模型系统，VNO 具有简单的蜂窝网络 具有少量干/祖细胞的结构，可在整个生命过程中产生新的感觉神经元。我们 选择使用这个简化的模型系统来研究控制神经发生、神经元分化的机制， 出生后生活中的细胞可塑性和稳态。 VNO 的神经上皮由两部分组成 选择性表达由两个犁鼻受体 (VR) 基因编码的受体的主要神经元类别 系列：V1R 和 V2R。虽然这两种神经元类型都起源于共同的祖细胞池，但 V1R 和 V2R 表达神经元定位于 VNO 内的不同区域并投射到附件的不同区域 嗅球。我们的中心假设指出转录因子 tfap2e (AP2e) 控制基础 VSN VNO 的身份、细胞组成及其与大脑的连接。我们建议犁鼻感觉 神经元保留了高水平的细胞可塑性，即使在终末期后也能重新编程 差异化。此外，我们建议通过以下方法建立骨形态发生蛋白 BMP 信号梯度 BMP 与胶原 IV (5, 6) 的亲和力，在基底膜中，启动基底分化程序，AP2e 整个生命过程中基础 VSN 遗传特性的表达和维持。我们的创新方法将 利用最先进的小鼠遗传学、2D 和 3D 成像、下一代测序、染色质 免疫沉淀（芯片）-seq、生物信息学和行为测试，以揭示定义的机制 并维持出生后动物化学感应神经元的特性。拟议的研究意义重大 了解特殊化学感应上皮中的关键基因调控网络以及如何变化 产后动物形态发生信号传导影响其细胞组成、组织稳态和神经元 连接性并确定人类化学感觉下降和神经变性的机制。 我们提出的研究结果可能会产生改善人类状况的治疗策略。 ！