The role of mouse ARL13B in cell diversification during spinal cord development

小鼠 ARL13B 在脊髓发育过程中细胞多样化中的作用

• 批准号: 7798148
• 负责人: TAMARA J. CASPARY
• 金额: $ 33.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798148
• 关键词: ADP-Ribosylation Factors; Anosmia; Biochemical; Biological; Blindness; Cell Differentiation process; Cell physiology; Cells; Cilia; Cilium Microtubule; Defect; Development; Diabetes Mellitus; Disease; Embryo; Epilepsy; Erinaceidae; Event; Exhibits; Failure; Functional disorder; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Human; Infertility; Kidney; Learning Disabilities; Link; Logic; Maintenance; Molecular; Monomeric GTP-Binding Proteins; Motor Neurons; Multiple Sclerosis; Mus; Mutant Strains Mice; Neural tube; Neurons; Obesity; Oligodendroglia; Organ; Organelles; Pathway interactions; Patients; Pattern; Perception; Phenotype; Play; Polydactyly; Proteins; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Situs Inversus; Specific qualifier value; Spinal Cord; Spinal cord injury; Stem cells; Structure; Tertiary Protein Structure; Testing; Time; To specify; Work; cell fate specification; cell growth; cell motility; cilium biogenesis; deafness; dysmyelination; human disease; improved; in vivo; mutant; nerve stem cell; neural circuit; novel; progenitor; research study; ADP-Ribosylation Factors; Anosmia; Biochemical; Biological; Blindness; Cell Differentiation process; Cell physiology; Cells; Cilia; Cilium Microtubule; Defect; Development; Diabetes Mellitus; Disease; Embryo; Epilepsy; Erinaceidae; Event; Exhibits; Failure; Functional disorder; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Human; Infertility; Kidney; Learning Disabilities; Link; Logic; Maintenance; Molecular; Monomeric GTP-Binding Proteins; Motor Neurons; Multiple Sclerosis; Mus; Mutant Strains Mice; Neural tube; Neurons; Obesity; Oligodendroglia; Organ; Organelles; Pathway interactions; Patients; Pattern; Perception; Phenotype; Play; Polydactyly; Proteins; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Situs Inversus; Specific qualifier value; Spinal Cord; Spinal cord injury; Stem cells; Structure; Tertiary Protein Structure; Testing; Time; To specify; Work; cell fate specification; cell growth; cell motility; cilium biogenesis; deafness; dysmyelination; human disease; improved; in vivo; mutant; nerve stem cell; neural circuit; novel; progenitor; research study

DESCRIPTION (provided by applicant): Recent studies have revolutionized the perception of cilia as an organelle of motility by showing cilia play roles in signaling events that control differentiation and cell growth. This proposal combines genetic, biochemical, molecular and cell biological approaches in order to understand how cilia signal and specify cell fate in the developing spinal cord by studying a protein, ARL13B. Mice deficient for ARL13B have defects in cell specification in the spinal cord due to a function of ARL13B in cilia. The proposed experiments in Aim 1 will genetically determine if ARL13B acts in the established signaling pathways that initially specify neural cell fate. Aim 2 will define how and when ARL13B is required in the neural progenitor cells that develop as motor neurons and subsequently as oligodendrocytes. The goal of Aim 3 is to relate the function of ARL13B in cell fate specification to its function in cilia by defining the functional domains that regulate ARL13B localization and by identifying interacting proteins. Taken together these results will provide new understanding of the role of cilia proteins in cell specification. The fundamental role ciliary proteins play in basic cellular functions is underscored by the diverse spectrum of phenotypes exhibited by patients with defects in these proteins. Obesity, situs inversus, infertility, diabetes, polydactyly, renal dysfunction, learning disabilities, epilepsy, deafness, anosmia and blindness are all seen in patients with defective cilia and are thought to result from failures in the formation, motility and signaling ability of cilia. By establishing the mechanism through which ARL13B functions in ciliogenesis and connecting it to the role of ARL13B in signaling to specify spinal cord cell fates the proposed work will provide a better understanding of motor neuron and oligodendrocyte development that can impact the treatment of dysmyelinating diseases such as multiple sclerosis as well as spinal cord injury. Given the direct connections between the signaling pathways that govern cell choice and the human disease states in which the same pathways are disrupted, this proposed work has high potential to improve human health

描述（由申请人提供）：最近的研究通过表明纤毛在控制分化和细胞生长的信号事件中发挥作用，彻底改变了纤毛作为运动的感知。该建议结合了遗传，生化，分子和细胞生物学方法，以了解纤毛信号如何通过研究蛋白质ARL13B来理解发育中的脊髓中细胞命运。由于纤毛中ARL13B的功能，缺乏ARL13B的小鼠在脊髓中的细胞规范中存在缺陷。 AIM 1中提出的实验将基因确定ARL13B是否在最初指定神经细胞命运的已建立的信号通路中起作用。 AIM 2将在神经祖细胞中定义如何以及何时需要ARL13B作为运动神经元发展，然后以少突胶质细胞为单位。 AIM 3的目的是通过定义调节ARL13B定位并识别相互作用蛋白质的功能域，将ARL13B在细胞命运规范中的功能与其在CILIA中的功能联系起来。结合这些结果将提供对纤毛蛋白在细胞规范中的作用的新理解。睫状蛋白在基本细胞功能中起着基本作用，这是由于这些蛋白质缺陷的患者表现出的各种表型而强调。肥胖，现场逆向，不育，糖尿病，多态，肾功能障碍，学习障碍，癫痫，耳聋，厌恶和失明都在有缺陷的纤毛患者中都可以看到，并且被认为是由于纤毛的形成，动力和信号能力而导致的。通过建立ARL13B在纤毛生成中起作用的机制，并将其与ARL13B在信号传导中的作用连接起来指定脊髓细胞命运的作用，将提供对运动神经元和寡胶质细胞发育的更好理解，从而可以影响诸如多发性硬化性脊髓症以及脊髓质子损伤的差异性疾病。鉴于控制细胞选择的信号通路与相同途径中断的人类疾病状态之间的直接连接，这项拟议的工作具有改善人类健康的巨大潜力