Function of ceruloplasmin in the nervous system development

铜蓝蛋白（Ceruloplasmin， CP）是一种具有氧化酶、氧化酶和抗氧化活性的多功能铜蛋白。它是铁代谢的重要调节剂。CP由肝脏分泌，是循环铜的主要载体。这种蛋白质也在大脑中合成，这一发现引起了人们极大的兴趣，因为一些神经退行性疾病与铁沉积有关。我们之前的研究表明，CP在体外可以保护神经元免受氧化应激。我们最近观察到CP在体外与P19胚胎干细胞新分化的神经元结合并诱导其聚集。神经聚集作用涉及细胞外丝氨酸蛋白酶活性，并伴随有特定的螺旋蛋白裂解。细胞外丝氨酸蛋白酶和reelin在发育中的大脑神经元层状排列中起着重要作用。因此，我们最近的结果表明CP在发育中的神经系统的神经元组织中的作用。我们的长期目标是证明和理解CP在发育中的神经系统中的功能。目前的目标是：(1)建立CP在体内神经系统发育中的生理相关性；(2)确定CP在P19细胞系（一种合适的新生神经元模型）中的神经元作用机制。我们将比较正常和cp缺陷小鼠发育和成年脑中神经元层压和reelin的表达。药物和抗体将用于P19细胞模型，以确定信号通路和涉及神经聚集和卷曲蛋白切割的蛋白水解活性。我们还将进一步表征CP与神经元的结合。我们的研究将有助于确定CP在发育中的神经系统中的功能。它们可以帮助理解一些神经组织紊乱的病因，如癫痫、精神分裂症、自闭症和情绪障碍。

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.