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

我们发现了TGF-β超家族的新成员GDF-15。GDF-15在上皮、外分泌腺、肾脏和胎盘中高度表达。GDF-15 mRNA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。我们已经表明，GDF-15是多巴胺能黑质纹状体神经元在体外和体内的一种有效的神经营养因子。我们培育了一只GDF-15-/- laczknockin小鼠，其寿命和繁殖正常。我们有初步的证据表明，突变小鼠表现出出生后运动神经元的丧失和外周轴突的髓鞘化。我们建议深入研究这一表型的细节。我们将研究运动、感觉和交感神经元经历神经元死亡的程度、时间进程和受影响的群体，以及隐含的机制。机制背后的高髓鞘表型将研究使用形态学，生化和细胞培养方法。伴有雪旺细胞特异性GDF-15缺失的小鼠将有助于阐明GDF-15突变型髓鞘形成表型是否是细胞自主的。我们希望能深入了解GDF-15在调节外周髓鞘形成和神经元存活中的新作用，并可能了解髓鞘形成和神经元死亡之间的相互依赖性。

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.