Genetic analysis of the neurotrophin receptor p75 in neural development

神经营养蛋白受体 p75 在神经发育中的遗传分析

• 批准号: 7529899
• 负责人: KUO-FEN LEE
• 金额: $ 41.89万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529899
• 关键词: Adult; Afferent Neurons; Affinity; Alzheimer' s Disease; Binding; Birth; Brain-Derived Neurotrophic Factor; Calcitonin Gene-Related Peptide; Cell Death; Cells; Class; Complement; Complex; Coupled; Data; Dependence; Development; Developmental Process; Embryo; Embryonic Development; Ephrin-A5; Epithelial; Family; GDNF gene; Genes; Genetic; Goals; Growth; Individual; Inositol; Intrinsic factor; Isolectin; Label; Ligands; Link; Localized; MAP Kinase Gene; Mediating; Modality; Molecular; Mus; Mutant Strains Mice; Myelin; NGFR Protein; NTF3 gene; Natural regeneration; Nerve; Nerve Growth Factor Receptors; Nerve Growth Factors; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropeptides; Neurotrophin 3; Nociception; Numbers; Peptides; Peripheral; Peripheral Nervous System Diseases; Phase; Population; Public Health; Receptor Protein-Tyrosine Kinases; Retinal Ganglion Cells; Role; Schwann Cells; Sensory; Sensory Ganglia; Signal Pathway; Signal Transduction; Specificity; Spinal; Spinal Ganglia; Staging; Substance P; System; Therapeutic; cell type; chronic pain; design; genetic analysis; human disease; inhibitor/antagonist; insight; interest; member; mutant; neurodevelopment; neuron loss; neuronal cell body; neurotrophic factor; neurotrophin 4; neurturin; persephin; postnatal; promoter; receptor; sensory system; size; sortilin; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the role of the neurotrophin receptor p75 in neural development and regeneration. Although initially identified for its ability to bind neurotrophins, p75 serves as a critical co-receptor to transduce multiple signaling pathways in neural development and function. For example, it is a co-receptor for glycosyl-phosphophatidyl inositol (GPI)-linked NgR and ephrinA5. We have been using the dorsal root ganglion (DRG) sensory neuron system to understand the role of p75 in neural development. DRG neurons are classified by multiple criteria including sizes, neuropeptides, trophic factor-dependence and sensory modalities. Sensory neuron development has embryonic and postnatal phases and is controlled by both extrinsic and intrinsic factors. We previously showed that 50% of DRG neurons are lost in p75 null mutants at birth. Because p75 is expressed in neurons, Schwann and target cells involved in the development of DRG sensory system, we generated p75 conditional mutant mice via the Cre-LoxP system (p75 floxed mice) to understand the role of p75 in these individual cell types. To delete the p75 gene in neurons, we crossed p75 floxed mice with mice expressing Cre under the control of the Islet1 promoter. In contrast to p75 null mutants, there is no DRG neuronal loss in these conditional mutants at birth. However, 20% of total DRG neurons are lost in adult mutants, including a significant number of glial cell-derived neurotrophic factor (GDNF)-dependent c-Ret+IB4+ nociceptive neurons. GDNF-dependent survival of postnatal p75-deficient DRG neurons is markedly decreased, suggesting that p75 is required for GDNF signaling. Preliminary results showed that p75 and GPI-linked GDNF receptor 11/12 (GFR11) and c-Ret are co-localized on DRG neurons and form a GDNF- dependent complex. Furthermore, p75 increases sensitivity of GDNF-induced MAPK Erk1/2 activation in transfected HEK 293 cells. To further understand the cellular and molecular mechanisms of p75-dependent signaling pathways in neural development, three specific aims are proposed. Aim 1 is to determine the role of p75 in neurons, epithelial and Schwann cells during embryonic spinal sensory neuron development. Aim 2 is to determine the role of p75 in nonpeptidergic neuron development. Aim 3 is to determine the role of p75 in GDNF signaling. PUBLIC HEALTH RELEVANCE: P75 may serve as a co-receptor to integrate multiple signaling pathways to regulate diverse cellular activities and is implicated in multiple human diseases in both peripheral and central nervous systems. The results from the present study will provide insights into designing therapeutic strategies to treat neurodegenerative diseases and peripheral neuropathy, including debilitating Alzheimer's Disease and chronic pain.

描述（由申请人提供）：该项目的长期目标是了解神经营养蛋白受体 p75 在神经发育和再生中的作用。尽管最初发现 p75 具有结合神经营养素的能力，但 p75 作为转导神经发育和功能中多种信号通路的关键共受体。例如，它是糖基磷脂酰肌醇 (GPI) 连接的 NgR 和 ephrinA5 的共受体。我们一直在使用背根神经节 (DRG) 感觉神经元系统来了解 p75 在神经发育中的作用。 DRG 神经元按照多种标准进行分类，包括大小、神经肽、营养因子依赖性和感觉方式。感觉神经元发育有胚胎期和产后期，并受外在和内在因素控制。我们之前表明，p75 无效突变体在出生时有 50% 的 DRG 神经元丢失。由于 p75 在参与 DRG 感觉系统发育的神经元、雪旺细胞和靶细胞中表达，因此我们通过 Cre-LoxP 系统生成了 p75 条件突变小鼠（p75 floxed 小鼠），以了解 p75 在这些个体细胞类型中的作用。为了删除神经元中的 p75 基因，我们将 p75 floxed 小鼠与在 Islet1 启动子控制下表达 Cre 的小鼠杂交。与 p75 无效突变体相比，这些条件突变体在出生时没有 DRG 神经元损失。然而，成年突变体中 20% 的 DRG 神经元总数丢失，其中包括大量胶质细胞源性神经营养因子 (GDNF) 依赖性 c-Ret+IB4+ 伤害性神经元。出生后 p75 缺陷的 DRG 神经元的 GD​​NF 依赖性存活显着降低，表明 p75 是 GDNF 信号传导所必需的。初步结果表明，p75 和 GPI 连接的 GDNF 受体 11/12 (GFR11) 和 c-Ret 共定位于 DRG 神经元，并形成 GDNF 依赖性复合物。此外，p75 增加转染 HEK 293 细胞中 GDNF 诱导的 MAPK Erk1/2 激活的敏感性。为了进一步了解神经发育中 p75 依赖性信号通路的细胞和分子机制，提出了三个具体目标。目标 1 是确定 p75 在胚胎脊髓感觉神经元发育过程中神经元、上皮细胞和雪旺细胞中的作用。目标 2 是确定 p75 在非肽能神经元发育中的作用。目标 3 是确定 p75 在 GDNF 信号传导中的作用。 公共健康相关性：P75 可能作为辅助受体整合多种信号通路来调节不同的细胞活动，并与外周和中枢神经系统的多种人类疾病有关。本研究的结果将为设计治疗神经退行性疾病和周围神经病变（包括使人衰弱的阿尔茨海默病和慢性疼痛）的治疗策略提供见解。