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

基本信息

批准号：
10532370
负责人：
Paolo E Forni
金额：
$ 34.76万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-04 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532370
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 Bone Morphogenetic Proteins Brain Cells Cellular Structures Characteristics Collagen Type IV DNA Sequence Alteration Data Defect Dementia Detection Disease Ectopic Expression Embryonic Development Environmental Risk Factor Epithelium 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 Neurodegenerative Disorders Neurologic Dysfunctions Neuronal Differentiation Neurons Olfactory Epithelium Olfactory Pathways Olfactory dysfunction Parkinson Disease Patients Pattern Pharmaceutical Preparations Pheromone Population Quality of life Receptor Gene Research Rodent Role Schizophrenia Sensory Signal Transduction Site Sorting Specific qualifier value Structure Symptoms Testing Therapeutic Three-Dimensional Imaging Tissues United States National Institutes of Health Vertebrates Work behavior test cell type chromatin immunoprecipitation differential expression gene regulatory network improved inducible Cre 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 cells symptom treatment transcription factor transcriptome vomeronasal organ

项目摘要

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。由特定基因组的表达来定义神经同一性如何启动和维持是核心。了解神经退行性疾病经常发生的分子原因。衰老、代谢紊乱和许多神经系统疾病，包括抑郁症、帕金森病、了解多发性硬化症、精神分裂症和痴呆症的信号控制终末分化，嗅觉神经元的表达模式、可塑性和稳态将填补我们的知识空白。拟议的研究将确定神经身份、轴突靶向和稳态的关键机制我们的总体目标将描述分子连接。犁鼻器（VNO）是嗅觉缺陷和神经功能障碍之间的一个特殊器官。嗅觉子系统负责检测信息素，而人类没有功能性 VNO。嗅觉上皮与 VNO 具有一些共同特征，作为模型系统，VNO 具有简单的细胞。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。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， 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家族：V1R 和 V2R 虽然这两种神经类型都起源于共同的祖细胞池，V1R 和 V2R。 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我们的中心假设指出转录因子 tfap2e (AP2e) 控制基础 VSN。我们提出犁鼻感觉神经元的身份、细胞组成及其与大脑的连接。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此外，我们建议通过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 我们的创新方法将在整个生命过程中表达和维持基础 VSN 遗传特性。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身份。这项研究具有重要意义。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。！

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Following the p63/Keratin5 basal cells in the sensory and non-sensory epithelia of the vomeronasal organ.

犁鼻器感觉和非感觉上皮细胞中的 p63/Keratin5 基底细胞。

DOI：
10.1002/dvg.23596
发表时间：
2024-04-01
期刊：
Genesis
影响因子：
1.5
作者：
Noah M. LeFever;R. R. Katreddi;Nikki M. Dolphin;Nick A. Mathias;P. Forni
通讯作者：
P. Forni

Sociosexual behavior requires both activating and repressive roles of Tfap2e/AP-2ε in vomeronasal sensory neurons.

社会性行为需要 Tfap2e/AP-2μ 在犁鼻感觉神经元中的激活和抑制作用。

DOI：
发表时间：
2022-09-16
期刊：
影响因子：
7.7
作者：
Lin, Jennifer M;Mitchell, Tyler A;Rothstein, Megan;Pehl, Alison;Taroc, Ed Zandro M;Katreddi, Raghu R;Parra, Katherine E;Zuloaga, Damian G;Simoes;Forni, Paolo Emanuele
通讯作者：
Forni, Paolo Emanuele

Notch signaling determines cell-fate specification of the two main types of vomeronasal neurons of rodents.

Notch 信号传导决定了啮齿动物两种主要类型的犁鼻神经元的细胞命运规范。

DOI：
发表时间：
2022-07-01
期刊：
影响因子：
0
作者：
Katreddi, Raghu Ram;Taroc, Ed Zandro M;Hicks, Sawyer M;Lin, Jennifer M;Liu, Shuting;Xiang, Mengqing;Forni, Paolo E
通讯作者：
Forni, Paolo E

Automated quantification of vomeronasal glomeruli number, size, and color composition after immunofluorescent staining.

免疫荧光染色后自动定量犁鼻肾小球数量、大小和颜色成分。

DOI：
发表时间：
2021
期刊：
影响因子：
3.5
作者：
Bahreini Jangjoo, Shahab;Lin, Jennifer M;Etaati, Farhood;Fearnley, Sydney;Cloutier, Jean;Khmaladze, Alexander;Forni, Paolo E
通讯作者：
Forni, Paolo E

Smad4-dependent morphogenic signals control the maturation and axonal targeting of basal vomeronasal sensory neurons to the accessory olfactory bulb.

Smad4 依赖性形态发生信号控制基底犁鼻感觉神经元的成熟和轴突靶向辅助嗅球。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Naik, Ankana S;Lin, Jennifer M;Taroc, Ed Zandro M;Katreddi, Raghu R;Frias, Jesus A;Lemus, Alex A;Sammons, Morgan A;Forni, Paolo E
通讯作者：
Forni, Paolo E