| 'The developing neuroepithelium is a mosaic of progenitor cell types, each destined for a particular fate and place in the mature brain. Each progenitor must make a decision to divide, to differentiate, or to die. Determining what molecular and genetic cues govern this process is at the heart of developmental neurobiology. This dissertation seeks to elucidate how immature cortical progenitors in the neuroepithelium at the peak period of neurogenesis either undergo programmed cell death, or differentiate along a neuronal lineage. The work outlined here has utilized prenatal alcohol exposure in a murine model to perturb normal brain development, in the hopes that by elucidating the mechanisms by which alcohol causes brain damage, the normal processes of development will become clearer. Heavy prenatal alcohol exposure can result in a spectrum of physical abnormalities and growth deficiencies, collectively known as the Fetal Alcohol Spectrum Disorder (FASD). Historically, much of the research on gestational exposure to alcohol has focused on cell loss as a mechanism of alcohol-induced damage. Chapter 2 of this document presents evidence that cortical progenitors during the peak period of murine neurogenesis are resistant to alcohol-induced apoptosis. In fact, alcohol exposure dramatically suppresses autophagy, a form of programmed cell death that has been implicated in differentiation. Cortical progenitors expressing the hematopoietic stem cell antigen CD 117 represent a more differentiated subset within the developing neuroepithelium. Treatment of CD 117-positive cells did not result in significant apoptosis. Quantitative PCR analysis of ethanol-treated CD 117-positive and CD 117-negative progenitors revealed that ethanol treatment may predispose these cells to premature differentiation, thereby depleting the proliferating stem cell pool. |
