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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. !

摘要神经系统由数千种不同类型的神经细胞组成。神经元的同一性和连接性是由特定基因电池的表达来定义的。神经元同一性是如何启动和维持的，这是中心了解神经退行性疾病的分子病因。嗅觉功能障碍经常发生在衰老、代谢障碍和许多神经疾病方面，包括抑郁症、帕金森氏症、多发性硬化症、精神分裂症和痴呆症。了解是什么信号控制着终端分化，嗅觉神经元的表达模式、可塑性和动态平衡将填补知识的一个关键空白。我们的拟议的研究将确定神经元识别、轴突靶向和动态平衡的关键机制。一种特殊的化学感官上皮。我们的总体目标将描绘出分子之间的联系嗅觉缺陷和神经功能障碍之间的关系。犁鼻器(VNO)是一种特殊的嗅觉子系统负责检测信息素。虽然人类没有功能性的VNO，但人类嗅觉上皮具有VNO的某些特征。作为一个模型系统，VNO有一个简单的蜂窝具有少量干细胞/祖细胞的结构，可在一生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、出生后生命中的细胞可塑性和动态平衡。迷走神经的神经上皮由两部分组成。选择性表达由两个犁鼻受体基因编码的受体的主要神经元类型家庭：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V1R 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。我们的中心假设是转录因子tfap2e(AP2e)控制基础VSN VNO的身份、细胞组成及其与大脑的连接。我们认为犁鼻感受器神经元保持着高度的细胞可塑性，这使得它们即使在终止后也可以重新编程。差异化。此外，我们提出骨形态发生蛋白BMP信号梯度是由 BMP与基底膜中的IV型胶原(5，6)有亲和力，启动基础分化程序AP2e 在整个生命过程中表达和维持VSNs的基本遗传特性。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，以揭示并维持出生后动物的化学感觉神经元的特性。这项拟议的研究具有重要意义为了了解特殊的化学感觉上皮中的关键基因调控网络以及如何变化出生后动物的形态发生信号影响其细胞组成、组织动态平衡和神经元连接，并确定人类化学感觉下降和神经退化的机制。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。好了！

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）

Mechanisms underlying pre- and postnatal development of the vomeronasal organ.

DOI：
10.1007/s00018-021-03829-3
发表时间：
2021-06
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
0
作者：
Katreddi RR;Forni PE
通讯作者：
Forni PE

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

DOI：
10.1242/dev.200448
发表时间：
2022-07-01
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
通讯作者：

GnRH-1 Neural Migration From the Nose to the Brain Is Independent From Slit2, Robo3 and NELL2 Signaling.

GnRH-1 从鼻子到大脑的神经迁移独立于 Slit2、Robo3 和 NELL2 信号传导。

DOI：
10.3389/fncel.2019.00070
发表时间：
2019
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
Taroc,EdZandroM;Lin,JenniferM;Tulloch,AlastairJ;Jaworski,Alexander;Forni,PaoloE
通讯作者：
Forni,PaoloE

Androgen Regulation of Corticotropin Releasing Factor Receptor 1 in the Mouse Brain.

DOI：
10.1016/j.neuroscience.2022.04.005
发表时间：
2022-05-21
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Rybka, Krystyna A.;Sturm, Kassandra L.;De Guzman, Rose M.;Bah, Saoudatou;Jacobskind, Jason S.;Rosinger, Zachary J.;Taroc, Ed Zandro M.;Forni, Paolo E.;Zuloaga, Damian G.
通讯作者：
Zuloaga, Damian G.

Identifying Isl1 Genetic Lineage in the Developing Olfactory System and in GnRH-1 Neurons.

在发育中的嗅觉系统和GNRH-1神经元中鉴定ISL1遗传谱系。