The overall goal of this project is to understand the molecular mechanisms controlling the formation of neurites during the growth and differentiation of neurons of the central nervous system. These investigations focus on the stimulation of neurite extension by a polypeptide growth factor, S100beta, whose structure has been determined. S100beta is an acidic protein of mass 21,102 that consists of a parallel disulfide dimer of two identical subunits, each of 91 amino acids. A full-length cDNA has been isolated, and cloned in a mammalian expression vector. The expression of S100beta in transfected COS cells results in full length and biologically active protein. S100beta appears to be released from astrocytes via a cAMP related mechanism, and acts on neurons via a specific, high affinity receptor. Using molecular probes for protein, mRNA, and biological activity, S100beta has been shown to be elevated >20 fold in the temporal lobe, including hippocampus, in Alzheimer's disease compared to age matched controls. Similarly, increased expression and action of S100beta in the developing nervous system suggests that the factor normally causes outgrowth of neurites from serotonergic neurons of the brainstem that innervate the hippocampus. The specific objectives for the project are: 1) To characterize the neuronal receptor for S100beta; 2) To analyze the regulation of the neuronal S100beta receptor in the brain; and 3) To investigate the role of S100beta in signalling protein kinase responses in neurons. The proposed project is a continuation of ongoing research that has established the presence of a significant neurotrophic factor in the central nervous system using a multidisciplinary approach of protein biochemistry, cellular neurobiology, and molecular biology. This research has yielded valuable information, concerning degenerative disorders of the central nervous system as well as contributed to our understanding of the normal differentiation of neurons.
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