Expression of transforming growth factor-beta in developing rat cerebral cortex: effects of prenatal exposure to ethanol.

The effects of prenatal ethanol exposure on the spatiotemporal expression of transforming growth factor-beta (TGFbeta) and its receptors in developing rat cerebral cortex in vivo were examined. Pregnant Long-Evans rats were fed ad libitum with a diet containing ethanol from gestational day (G) 6 through G21 or were pair fed an isocaloric nonalcoholic liquid diet. A quantitative immunoblotting study showed that expression of TGFbeta ligands was differentially affected by ethanol; ethanol decreased TGFbeta1 expression fetally and in the mature cortex and increased TGFbeta2 at most ages. A complementary immunohistochemical experiment generated similar results so far as the timing of ligand expression was concerned. In both control and ethanol-treated rats, TGFbeta1 was expressed by cells in the two neocortical proliferative zones and neurons in the cortical plate. TGFbeta2 was expressed principally by radial glia and astrocytes in developing rats. In the adult, both ligands were expressed by glia and neurons. Ethanol virtually eliminated the TGFbeta1 expression in the perinatal subventricular zone. The TGFbeta2-positive radial glial labeling was transient and was lost earlier in ethanol-treated neonates than in controls. Concomitantly, the appearance of TGFbeta2-positive glia occurred earlier in the ethanol-treated rats. The expression of only one receptor (TGFbetaIr) was affected by ethanol; it was increased during the pre- and early postnatal periods. TGFbetaIr was expressed by glia perinatally and by all cell types in weanlings. As with TGFbeta2, ethanol exposure promoted the loss of TGFbetaIr expression in radial glia and the precocious expression among astrocytes. TGFbetaIIr was expressed primarily by neurons. Thus, TGFbeta ligands and receptors are strategically placed both in time and space to regulate cell proliferation and migration. Ethanol, which affects both of these processes, has marked effects on the TGFbeta system and apparently promotes the early transformation of radial glia into astrocytes. Copyright 2003 Wiley-Liss, Inc.