Ethanol Affects Transforming Growth Factor β1-Initiated Signals: Cross-Talking Pathways in the Developing Rat Cerebral Wall

Abstract

TGF␤1 regulates early cortical development by moving young neurons from the proliferative population and promoting their migration. Altered TGF␤1-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 TGF␤1 signals through cross-talking Smad2/3 and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways and that ethanol simulates these TGF␤1-initiated signals. Slices generated from the telencephalons of 17-d-old rat fetuses were treated with TGF␤1 (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 TGF␤1, 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 TGF␤1-responsive pathways. TGF␤1-induced effects were primarily in the S/VZ, whereas ethanol induced activation in both compartments. In summary, TGF␤1 activates two separate pathways (Smad2/3 and ERK1/2) that actively interact. Ethanol simulates TGF␤1-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.

Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol

“…S2C). This finding is consistent with the previous observations in the developing rat cortex, which suggested that altered TGF-β signaling in response to mFAE may be involved in abnormal cell proliferation and neuronal migration (15,24,25). We also obtained a set of molecular clues to the potential defects in cortical development by mFAE, such as "PI3 kinase pathway" and "Notch signaling pathway" ( Table 2).…”

“…In addition, ethanol has a technical advantage as a powerful pharmacological agent, which can mask subtle alterations of gene expression caused by heterogeneous genetic backgrounds among human samples. Above all, there is a comprehensive list of experimental literature on the effects of ethanol on the rodent brain (9)(10)(11)(12)(13)(14)(15).…”

“…The mouse cerebral cortex is highly vulnerable to ethanol exposure in the midgestational period, which is associated with extensive neurogenesis and neuronal migration to the cerebral cortex (9)(10)(11)(12)(13)(14)(15). A comparable stage in the human cerebral cortex is in the early midgestational period during which a large number of neurons migrate the longest distance to the superficial cortical layers (16,17).…”

Activation of MAPK/PI3K/SMAD Pathways by TGF-β1 Controls Differentiation of Radial Glia into Astrocytes in vitro

“…Cooperation between the noncanonical and canonical TGF-β 1 pathways has been recognized in different cell types [30,31,32] including radial glia [65]. The presence of a SMAD-binding domain has not yet been identified within the GFAP gene promoter, and the effects of SMADs on this gene have been suggested to result from cooperation with other protein partners such as STATs in neural progenitor cells [19,66,67,68].…”

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

“…Several studies have identified effects of low amounts of alcohol exposure on the development of serotonergic neurons (Sari and Zhou, 2004;Zhou et al, 2003;Zhou et al, 2005), and suggested that these types of defects in the ontogeny of a specific neurotransmitter system may underlie the more 'subtle' deficits observed in human children diagnose with Alcohol Related Neurodevelopmental Disorder, rather than fullblown FAS (Zhou et al, 2003). Ethanol exposure disrupts the proliferation of glia and neuronal precursors in the developing central nervous system (Luo and Miller, 1998;Miller, 2007;Miller and Hu, 2009;Powrozek and Miller, 2009) and can dramatically alter behavior (Hellemans et al, 2010;Valenzuela et al, 2012). Transcriptional analyses of gene products regulated by fetal ethanol exposure in both mouse and human cells also highlight genes related to neural development, such as cell proliferation, neuronal migration, and differentiation (Hashimoto-Torii et al, 2011;Hicks et al, 2010).…”