Involvement of Gli proteins in undifferentiated state maintenance and proliferation of embryonic stem cells

摘要

Although several important transcription factors, such as STAT3, Oct3/4, Sox2, and Nanog, have been identified for the self-renewal of mouse embryonic stem (ES) cells, the molecular mechanism behind ES cell self-renewal is not fully understood. In this study, I found that transcriptional activators Glil and Gli2 are highly expressed in undifferentiated ES cells and that their expression is downregulated upon differentiation. The expression of Glil and Gli2 was also reduced by the suppression of either Oct3/4 or Nanog, suggesting that Glil and Gli2 are downstream molecules of these transcription factors. Forced expression of a dominant-negative mutant of Gli2, which inhibits both Glil and Gli2, induced the disruption of compact colony formation, downregulation of Sox2， and upregulation of differentiation marker genes, Gata4 and Cdx2. Furthermore, the Gli2 mutant reduced the growth rate of ES cells. These results suggest that Glil and Gli2 are positive regulators of undifferentiated state maintenance and proliferation in ES cells.