RETINOIC ACID REGULATES THYMOSIN BETA-10 LEVELS IN RAT NEUROBLASTOMA-CELLS

A small acidic polypeptide, termed thymosin beta-10, has been identified and is present in the nervous system of the rat by the ninth day of gestation. Thymosin beta-10 levels rise during the remaining days of life in utero, and then decline to nearly undetectable values between the second and fourth week post partum. The present study investigates the possible developmental signals and mechanisms that might regulate the expression of thymosin beta-10 during neuroembryogenesis. Many cell lines derived from tumors of the central nervous system express thymosin beta-10, as well as its homologue gene product, thymosin beta-4. Because some of these cell lines respond to exogenously applied agents by increasing their apparent state of differentiation, we have determined whether thymosin beta-10 levels are coordinately modulated. In several neuroblastomas, including the B103 and B104 lines, retinoic acid elicits a time- and dose-dependent increase in the content of thymosin beta-10, but not that of thymosin beta-4. The increase in thymosin beta-10 polypeptide is associated with a marked increase in the specific mRNA encoding this molecule. The mRNA for thymosin beta-4 is unaffected by retinoic acid. This is in contrast with the situation in vivo, where the expression of both genes decreases after birth. Other agents that influence the morphology of B104 cells, such as phorbol esters and dibutyryl cyclic AMP, have no influence on beta-thymosin levels. A range of steroids, which like retinoids act upon nuclear receptors, was also inactive. The stimulatory action of retinoic acid is detectable within 4 h, and thymosin beta-10 peptide levels continue to rise for at least 4 days. The influence of the isoprenoid is fully reversible and exhibits structural specificity. We believe that this culture system is mimicking the early rising phase of thymosin beta-10 levels in brain and that endogenous retinoids may be candidate physiological regulators of this gene.