Neuronal migration is an essential aspect of normal fetal development. When this process is disrupted, as in the case of fetal alcohol exposure, neurons terminate their migration in ectopic locations in the cortex and, in some cases, continue their migration through to the pial layer resulting in heterotopias. Growth factors play a critical role in normal CNS development. One of these, TGFbeta, has been shown to be important for various developmental processes including the promotion of neuronal migration. The proposed studies will focus on the role of TGFbeta signaling cascade (binding and activation of the receptor as well as activation of downstream signaling molecules) in mediating the effects of ethanol exposure on migrating neurons destined for the cerebral cortex, an area which has been shown to be particularly susceptible to prenatal alcohol exposure. The unique feature of these anatomical studies come from the comparison of the genomic and proteomic expression patterns in ectopic cells in the marginal zone and heterotopias to cogenerated cohorts in the cortical plate of both ethanol-treated and/or TGFbeta1- treated cultures. From these data we will determine genes and/or proteins that are differentially expressed in ethanol treated animals leading to deficits in either the initiation (intermediate zone) or termination (marginal zone vs. heterotopia) of migration. These studies will then help to elucidate the mechanism by which TGFbeta1 regulates neuronal migration within the normally developing CNS and will offer important insight into the mechanisms underlying the deficits seen in cortical neuronal migration following alcohol exposure.
|Powrozek, Teresa A; Miller, Michael W (2009) Ethanol affects transforming growth factor beta1-initiated signals: cross-talking pathways in the developing rat cerebral wall. J Neurosci 29:9521-33|