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

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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.