Transferrin and the growth-promoting effect of nerves

In addition to its role in the activity of specialized proteins such as hemoglobin and myoglobin, iron is required as a cofactor in several important enzymes common to most animal cells. One such enzyme, ribonucleotide reductase, which regulates the production of deoxyribonucleotides during DNA synthesis, requires a continuous supply of iron to maintain its activity throughout the process of DNA replication. The mechanism by which animal cells normally acquire iron involves receptor-mediated uptake of iron-loaded transferrin, followed by release of apotransferrin. The density of transferrin receptors on the cell surface is greatly increased in rapidly dividing normal and neoplastic cells. Various mitogens and certain organogenic tissue interactions have been shown to induce the appearance of transferrin receptors, signalling the onset of DNA replication. Interference with this process of iron delivery causes the rapid arrest of cell cycling, frequently during the S phase itself, which underscores the importance of iron for DNA replication. Although most circulating transferrin is synthesized in the liver and embryonic yolk sac, smaller quantities are produced in several other embryonic organs and certain other adult tissues. It has been suggested that local synthesis and/or release of transferrin supplies the iron required by rapidly growing cells in situations where the cells do not have ready access to adequate amounts of plasma transferrin due to incomplete development of the vasculature or the presence of blood-tissue barriers (Ekblom and Thesleff, 1985; Meek and Adamson, 1985). Oligodendrocytes and Schwann cells have been shown to synthesize and/or contain high concentrations of transferrin and these cells therefore may constitute a local source of this factor for neurons, whose growth and survival in vitro require transferrin. Transferrin in central and peripheral nervous tissues may be significant for the trophic or growth-promoting effect neurons exert on cells of certain tissues. Transferrin duplicates the activity of neural tissue or neural extracts on growth and development of cultured skeletal myoblasts from chick embryos and on proliferation of mesenchymal cells in blastemas from regenerating amphibian limbs, two systems that have been widely used in investigations of the growth-promoting influence of nerves. Moreover, removal of active transferrin from neural extracts, either with antibodies to transferrin or chelation of the iron, inhibits reversibly the effect of the extract in these developing systems. While the physiological significance of the extract in these developing systems.(ABSTRACT TRUNCATED AT 400 WORDS)