Function of ceruloplasmin in the nervous system development

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Ceruloplasmin (CP) is a multifunctional copper protein having ferroxidase, oxidase and antioxidant activities. It is an essential regulator of iron metabolism. CP is secreted by the liver and is the main carrier of circulating copper. This protein is also synthesized in the brain, a discovery of vivid interest since some neurodegenerative diseases are associated with iron deposits. Our previous studies showed that CP protects neurons against oxidative stress in vitro. We recently observed that CP binds, in vitro, to newly differentiated neurons from P19 embryonic stem cells and induces their aggregation. The neuroaggregative action involves an extracellular serine protease activity and is accompanied by a specific cleavage of the reelin protein. Extracellular serine proteases and reelin have a prominent role in the layered arrangement of neurons in the developing brain. Therefore, our recent results suggest a role of CP in neuronal organization of the developing nervous system. Our long term goal is to demonstrate and understand the function of CP in the developing nervous system. The present objectives are : (1) establish the physiological relevance of CP in the nervous system development in vivo, and (2) determine the mechanisms of the neuronal actions of CP in the P19 cell line, an appropriate model of nascent neurons. We will compare the neuronal lamination and the reelin expression in the developing and adult brains of normal and CP-deficient mice. Pharmacological agents and antibodies will be used in the P19 cell model to identify the signaling pathways and the proteolytic activities implicated in neuroaggregation and reelin cleavage. We will also further characterize the binding of CP to neurons. Our studies will contribute to define the funtion of CP in the developing nervous system. They could help understanding the etiology of some neuronal organization disorders such as epilepsy, schizophrenia, autism and mood disorders.