The primary purpose of this study is to investigate the role and mechanism of insulin like growth factor-II (IGF-II) in the nervous system. The identification of new neuritogenic factors, and the determination of their mechanisms, would significantly advance our understanding of nervous system development. IGF-II is a member of a new family of related neuritogenic polypeptides. Transcripts related to the pre-pro-IGF-II mRNA sequence are expressed in brain and other tissues. We propose, in this project period, to study more completely the expression of the IGF-II gene in various rat tissues during development, and following denervation. These studies will determine whether the temporal expression of IGF-II transcripts is consistent with innervation and maturation of target tissues, and reveal the intimate relationship between gene expression and innervation. The requirement of IGF-II for development of the sensory and sympathetic nervous system will be studied by treatment of neonatal rats with anti- IGF-II antiserum. The mechanism by which IGF-II enhances neurite formation will be studied in cultured sensory and sympathetic neurons from chick and rat, and in human neuroblastoma and rat pheochromocytoma cell lines. The mechanism of neurite outgrowth, in itself, is a major, incompletely solved problems, whose solution could profoundly influence the fundamental understanding of neurobiology, and impact on significant clinical issues. The levels of tubulin mRNA appear to be highly regulated by IGF-II, insulin and nerve growth factor in a variety of cell types, and correlate with neurite formation. We shall study whether tubulin mRNA expression is essential for neurite growth, document more completely its regulation by these factors, and study the mechanism for enhancement of tubulin mRNA levels. These studies serve to bridge the gap between neurite growth and attempts to identify the second messenger of neuritogenic polypeptides. Mice will be employed in this study as a source of nerve growth factor.
