Ethanol affects transforming growth factor beta1-initiated signals: cross-talking pathways in the developing rat cerebral wall.

TGFbeta1 regulates early cortical development by moving young neurons from the proliferative population and promoting their migration. Altered TGFbeta1-regulated signaling can lead to abnormal development underlying microencephaly and migratory defects as in attention deficit hyperactivity disorder, dyslexia, and fetal alcohol spectrum disorder. The present study tested the hypotheses that TGFbeta1 signals through cross-talking Smad2/3 and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways and that ethanol simulates these TGFbeta1-initiated signals. Slices generated from the telencephalons of 17-d-old rat fetuses were treated with TGFbeta1 (0 or 10 ng/ml), ethanol (0, 200, 400, or 800 mg/dl), and/or a pharmacological agent [to block phosphorylation of Smad2/3 (SB431542 or LY364947) or ERK1/2 (PD98059 or U0126)]. In some experiments, the proliferative compartment (the ventricular and subventricular zones; S/VZ) and the postproliferative compartment (intermediate zone/cortical plate/marginal zone) were examined separately. Smad2/3 phosphorylation increased following treatment with TGFbeta1, ethanol, and PD98059 (or U0126) plus ethanol. In contrast, SB431542 (and LY364947) blocked Smad2/3 activation and led to the phosphorylation of ERK1/2. These changes revealed cross talk between the two TGFbeta1-responsive pathways. TGFbeta1-induced effects were primarily in the S/VZ, whereas ethanol induced activation in both compartments. In summary, TGFbeta1 activates two separate pathways (Smad2/3 and ERK1/2) that actively interact. Ethanol simulates TGFbeta1-induced changes in these signaling systems. Each pathway is preferentially activated during specific developmental events: the Smad2/3 pathway is key for cells exiting from the cycling population and the ERK1/2 pathway is particularly inducible during neuronal migration.