Functions of Growth/Differentiation Factor-15 (GDF-15) in Neuron Survival and peripheral Myelination

生长/分化因子 15 (GDF-15) 在神经元存活和外周髓鞘形成中的功能

• 批准号: 40772513
• 负责人: Professor Dr. Klaus Unsicker
• 金额: --
• 依托单位: Institut für Anatomie und Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/40772513?language=en
• 关键词: Functions; Growth; Differentiation; Factor; 15

We have discovered GDF-15, a novel member of the TGF-β superfamily. GDF-15 is highly expressed in e.g. epithelia, exocrine glands, kidney, and placenta. GDF-15 mRNA and protein are also widely expressed in the CNS and peripheral nervous system, including sensory ganglia and Schwann cells. We have shown that GDF-15 is a potent neurotrophic factor for dopaminergic nigrostriatal neurons in vitro and in vivo. We have generated a GDF-15-/-LacZknockin mouse, whose lifespan and reproduction is normal. We have preliminary evidence that mutant mice display a postnatal loss of motoneurons and hypermyelination of peripheral axons. We propose to study in depth details of this phenotype. We shall investigate the extent, time course and affected populations of motor, sensory, and sympathetic neurons undergoing neuron death as well as mechanisms implied. Mechanisms underlying the hypermyelination phenotype will be studied using morphological, biochemical, and cell culture methods. Mice with Schwann cell specific deletions of GDF-15 will help to clarify whether the GDF-15 mutant myelination phenotype is cell-autonomous. We expect insight into novel roles of GDF-15 in the regulation of peripheral myelination and neuron survival, and, possibly, information on the interdepence of hypermyelination and neuron death.

我们发现了GDF-15，TGF-β超家族的新成员。GDF-15在例如上皮、外分泌腺、肾和胎盘中高度表达。GDF-15 mRNA和蛋白也广泛表达于CNS和周围神经系统，包括感觉神经节和雪旺细胞。我们已经表明，GDF-15是一种有效的神经营养因子多巴胺能黑质纹状体神经元在体外和体内。我们已经产生了GDF-15-/-LacZknockin小鼠，其寿命和繁殖正常。我们有初步的证据表明，突变小鼠显示出出生后运动神经元的损失和外周轴突的髓鞘形成。我们建议深入研究这种表型的细节。我们将研究运动、感觉和交感神经元死亡的程度、时间进程和受影响的群体以及隐含的机制。髓鞘形成过度表型的机制将采用形态学、生物化学和细胞培养方法进行研究。具有GDF-15的雪旺细胞特异性缺失的小鼠将有助于澄清GDF-15突变体髓鞘形成表型是否是细胞自主的。我们期望深入了解GDF-15在外周髓鞘形成和神经元存活调节中的新作用，并可能了解髓鞘形成过度和神经元死亡的相互依赖性。