Molecular Mechanisms of Cellular Differentiation in the Nervous System

神经系统细胞分化的分子机制

• 批准号: 8650923
• 负责人: SHANTHINI SOCKANATHAN
• 金额: $ 35.08万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650923
• 关键词: Ablation; Affect; Binding; Biochemical; Biochemical Genetics; Biochemistry; Biological Assay; Biological Models; Cells; Cleaved cell; Development; Disease; Electroporation; Enzymes; Exhibits; Family; Fibroblast Growth Factor; Future; GPI Membrane Anchors; Generations; Genes; Genetic; Glial Differentiation; Glycosylphosphatidylinositols; Goals; In Vitro; Ligands; Membrane; Molecular; Motor Neurons; Mus; Nervous System Physiology; Nervous system structure; Neuronal Differentiation; Oligodendroglia; Outcome; Pathway interactions; Physiological; Proteins; Role; Signal Pathway; Signal Transduction; Specificity; Spinal; Spinal Cord; System; Testing; Time; Tretinoin; Vertebrates; Work; base; developmental genetics; developmental neurobiology; extracellular; gain of function; gliogenesis; glycerophosphodiester phosphodiesterase; in vivo; insight; mutant; neurogenesis; notch protein; novel; oligodendrocyte lineage; overexpression; premature; prevent; progenitor; protein function; public health relevance; research study; translational approach

DESCRIPTION (provided by applicant): The major goals of this proposal are to understand the molecular basis of neuronal and glial differentiation in the developing nervous system. Here, the mechanisms that control sequential motor neuron and oligodendrocyte differentiation from a single progenitor domain (pMN) within the spinal cord will be investigated. GDE2, a six-transmembrane (6-TM) protein that contains an extracellular glycerophosphodiester phosphodiesterase (GDPD) domain is necessary and sufficient to induce motor neuron differentiation through GDPD activity. In this proposal, biochemical and in vivo approaches will be used to define the mechanism of GDE2 GDPD activity and identify potential physiological substrates of 6- TM GDPD enzymatic function. Strikingly, a second 6-TM GDE protein shows complementary expression to GDE2 that is coincident with oligodendrocyte generation. In vivo and in vitro approaches will be taken to test the function of this second GDPD regulatory system in oligodendrocyte specification, differentiation and maturation. Genetic ablation of GDE2 results in increased numbers of oligodendrocytes in the gliogenic period, suggesting that GDE2 might prevent the premature initiation of oligodendrocyte differentiation. This hypothesis will be tested using a combination of biochemical, genetic and functional approaches. Taken together, these studies will provide mechanistic insight into novel GDPD-dependent regulatory systems that control motor neuron and oligodendrocyte differentiation, and determine if they intersect to regulate the temporal control of neurogenesis and gliogenesis in the spinal cord.

描述（由申请人提供）：该提案的主要目标是了解发育中的神经系统中神经元和神经胶质分化的分子基础。在这里，将研究控制脊髓内单个祖细胞域 (pMN) 顺序运动神经元和少突胶质细胞分化的机制。 GDE2 是一种六次跨膜 (6-TM) 蛋白，含有细胞外甘油磷酸二酯磷酸二酯酶 (GDPD) 结构域，对于通过 GDPD 活性诱导运动神经元分化是必要且充分的。在本提案中，将使用生化和体内方法来定义 GDE2 GDPD 活性的机制并确定 6-TM GDPD 酶功能的潜在生理底物。引人注目的是，第二种 6-TM GDE 蛋白显示出与 GDE2 互补的表达，这与少突胶质细胞的生成同时发生。将采用体内和体外方法来测试第二个 GDPD 调节系统在少突胶质细胞规范、分化和成熟中的功能。 GDE2 的基因消除会导致胶质细胞生成期少突胶质细胞数量增加，这表明 GDE2 可能会阻止少突胶质细胞分化的过早启动。这个假设将被检验 结合使用生化、遗传和功能方法。总而言之，这些研究将为控制运动神经元和少突胶质细胞分化的新型 GDPD 依赖性调节系统提供机制见解，并确定它们是否交叉以调节脊髓中神经发生和胶质细胞生成的时间控制。