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: 10292450
• 负责人: Paolo E Forni
• 金额: $ 34.65万
• 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/10292450
• 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; 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; gene regulatory network; 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. !

总结 神经系统由数千种不同的神经细胞类型组成。神经元身份和连接性 是由特定基因组的表达决定的神经元的同一性是如何启动和维持的， 了解神经退行性疾病的分子原因。嗅觉功能障碍经常发生在 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差异， 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 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 一种特殊的化学感受上皮。我们的总体目标是描绘出 嗅觉缺陷和神经功能障碍之间的联系犁鼻器（vomeronasal organ，VNO）是一种专门的 嗅觉子系统负责检测信息素。虽然人类没有功能性VNO，但人类 嗅上皮与VNO具有某些共同特征。作为一个模型系统，VNO具有一个简单的蜂窝 具有少量干/祖细胞的结构，这些干/祖细胞在整个生命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， 细胞可塑性和产后生活中的稳态。VNO的神经上皮由两个细胞组成， 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 家族：V1 R和V2 R虽然这两种神经元类型都起源于共同的祖细胞库，但V1 R和V2 R都是神经元。 V2 R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是转录因子tfap 2 e（AP 2 e）控制基础VSN的 身份，VNO的细胞组成及其与大脑的连接。我们认为犁鼻感觉神经 神经元保留了高水平的细胞可塑性，即使在终末死亡后， 分化此外，我们提出，骨形态发生蛋白BMP信号梯度建立 BMP在基底膜中与胶原IV（5，6）的亲和力，启动基础分化程序，AP 2 e 在整个生命过程中表达和维持基础VSN的遗传特性。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， 并维持出生后动物中化学感受神经元的特性。所提出的研究是有意义的 以了解在一个专门的化学感觉上皮细胞的关键基因调控网络，以及如何改变 在出生后动物中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，并确定人类化学感觉下降和神经变性的潜在机制。 我们提议的研究结果可能会产生改善人类状况的治疗策略。 !