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

我们发现了转化生长因子-β超家族中的一个新成员--GDF15。GDF-15在上皮、外分泌腺、肾脏和胎盘中高表达。GDF-15mRNA和蛋白也广泛表达于中枢神经系统和周围神经系统，包括感觉神经节和雪旺细胞。我们已经证明GDF-15在体外和体内对多巴胺能黑质纹状体神经元是一种有效的神经营养因子。我们已经培育了一只GDF-15-/-LacZwnkkin小鼠，它的寿命和繁殖都是正常的。我们有初步证据表明，突变小鼠在出生后表现出运动神经元的丢失和外周轴突的高髓鞘形成。我们建议深入研究这种表型的细节。我们将调查经历神经元死亡的运动神经元、感觉神经元和交感神经元的范围、时间进程和受影响的群体，以及隐含的机制。高髓鞘形成表型的潜在机制将用形态、生化和细胞培养方法进行研究。雪旺细胞特异性缺失GDF-15的小鼠将有助于阐明GDF-15突变的髓鞘表型是否具有细胞自主性。我们期望深入了解GDF-15在调节外周髓鞘形成和神经元存活中的新作用，并可能提供关于超髓鞘形成和神经元死亡相互依赖的信息。

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.