Enforced Pax6 Expression Rescues Alcohol-Induced Defects of Neuronal Differentiation in Cultures of Human Cortical Progenitor Cells

Abstract

Alcohol is the most widely consumed substance of abuse, and its use during pregnancy can lead to serious disorders of brain development. The precise molecular action of alcohol on human brain development, however, is still unknown. We previously enriched multipotent progenitor cells, radial glia (RG) cells, from human fetal forebrain and demonstrated that they express transcription factor Pax6 that is necessary for their neurogenic fate. Enriched human fetal RG cells were maintained in vitro as either control or Pax6-expressing retrovirus infected cells. Cultures were treated with increasing doses of alcohol to evaluate Pax6 expression, proliferation, and differentiation of RG cells by immunocytochemistry, Western blot, and RT-PCR methods. In vitro treatment with alcohol reduced the expression of transcription factor Pax6 and proliferation of RG cells, which decreased neurogenesis. Consistent with this finding, the overexpression of Pax6 in RG cells under alcohol treatment rescued cell proliferation and restored the generation of neurons. In contrast to this effect on neurogenesis, the overexpression of Pax6 inhibits the generation of astroglia regardless of alcohol treatment, implying lineage-specific effects. These findings suggest that the effect of alcohol on human neurogenesis is partially due to the reduced expression of transcription factor Pax6 in RG cells.