Biomedical subjects

Julie A Siegenthaler

Publications and source records attributed to Julie A Siegenthaler.

4 recordsLinked to original sources

PubMed2005

Ethanol disrupts cell cycle regulation in developing rat cortex interaction with transforming growth factor beta1.

Ethanol is a potent teratogenic agent that disrupts several aspects of neuronogenesis, including the proliferation rate of cortical precursors. With regard to corticogenesis, possible targets of ethanol toxicity include soluble factors, like transforming growth factor beta1 (TGFbeta1), that regulate cortical growth and cell cycle proteins that control the kinetics of the cell cycle. The effect of ethanol on normal cell proliferation and TGFbeta1-regulated cell proliferation in the developing cortex was assessed using an organotypic slice culture model. Ethanol elongated the cell cycle, possibly through a decrease in the expression of G1 cell cycle protein cyclin D1. Further, ethanol exposure antagonized the anti-proliferative action of TGFbeta1 and blocked TGFbeta1-dependent increases in cell cycle inhibitor p21. Collectively, this evidence suggests that disruption of appropriate cell cycle protein expression and inhibition of TGFbeta1 activity are potential mechanisms underlying the effect of ethanol on cortical development.

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PubMed2005

Transforming growth factor beta 1 promotes cell cycle exit through the cyclin-dependent kinase inhibitor p21 in the developing cerebral cortex.

During cortical neurogenesis, cell proliferation and cell cycle exit are carefully regulated to ensure that the appropriate numbers of cells are produced. The antiproliferative agent transforming growth factor beta1 (TGFbeta1) and its receptors are endogenously expressed in proliferative zones of the developing cerebral cortex, thus implicating the growth factor in cell cycle regulation. The present study tested the hypothesis that TGFbeta1 promotes cell cycle exit in the cortical ventricular zone (VZ) through modulation of cell cycle protein expression, in particular cyclin D1 and the cyclin-dependent kinase inhibitors p27 and p21. Although it did not affect the length of the cell cycle, TGFbeta1 decreased the fraction of VZ-cycling cells by 21% and increased the number of VZ cells exiting the cell cycle a commensurate 24%. TGFbeta1 selectively increased the expression of p21 in the VZ. In addition, high p21 expression levels were observed in VZ cells as they exited the cell cycle, and TGFbeta1 increased the number p21-positive cells exiting the cell cycle. Collectively, these data show the following: (1) TGFbeta1 promotes cell cycle exit, (2) p21 upregulation is correlated with cell cycle exit, and (3) TGFbeta1-induced cell cycle exit is mediated by p21.

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PubMed2004

Ethanol induces heterotopias in organotypic cultures of rat cerebral cortex.

Abnormalities in the migration of cortical neurons to ectopic sites can be caused by prenatal exposure to ethanol. In extreme cases, cells migrate past the pial surface and form suprapial heterotopias or 'warts'. We used organotypic slice cultures from 17-day-old rat fetuses to examine structural and molecular changes that accompany wart formation. Cultures were exposed to ethanol (0, 200, 400 or 800 mg/dl) and maintained for 2-32 h. Fixed slices were sectioned and immunolabeled with antibodies directed against calretinin, reelin, nestin, GFAP, doublecortin, MAP-2 and NeuN. Ethanol promoted the widespread infiltration of the marginal zone (MZ) with neurons and the focal formation of warts. The appearance of warts is time- and concentration-dependent. Heterotopias comprised migrating neurons and were not detected in control slices. Warts were associated with breaches in the array of Cajal-Retzius cells and with translocation of reelin-immunoexpression from the MZ to the outer limit of the wart. Ethanol also altered the morphology of the radial glia. Thus, damage to the integrity of superficial cortex allows neurons to infiltrate the MZ, and if the pial-subpial glial barrier is also compromised these ectopic neurons can move beyond the normal cerebral limit to form a wart.

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PubMed2004

Transforming growth factor beta1 modulates cell migration in rat cortex: effects of ethanol.

Transforming growth factor (TGF) beta1 regulates cell migration of non-neural cells. Hence, two hypotheses were tested: (i) that TGFbeta1 affects cell migration and the expression of associated adhesion proteins in developing cortex; and (ii) that these effects are antagonized by ethanol. The effects of TGFbeta1 (2.5-40 ng/ml) and ethanol (400 mg/dl) on cell migration were examined in organotypic cultures from fetal rat brains. Migration was determined by tracing the movement of cells pulse-labeled with bromodeoxyuridine. Cell migration was altered by TGFbeta1 in a concentration-dependent manner: at low concentrations, cell migration was promoted whereas at high concentrations TGFbeta1 impeded migration. Ethanol treatment alone reduced the rate of migration. Interestingly, the rate of cell migration in slices treated with both TGFbeta1 and ethanol was the same as that in untreated cultures. The expression of cell adhesion proteins (nCAM, integrin alpha3, alphav and beta1) was differentially effected by TGFbeta1 and/or ethanol. TGFbeta1 increased the expression of these adhesion proteins in a progressive, concentration-dependent manner. Likewise, ethanol also increased adhesion protein expression, however, combined TGFbeta1 and ethanol treatment reduced expression. Collectively, the data show that TGFbeta1 alters cell migration in the developing cortex and that the TGFbeta1 system is a target of ethanol toxicity.

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