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研究発表を行った学会；
・第一回熊本大学グローバルCOE国際シンポジウム
　2008年1月16日(熊本)

タイトル；Stage-dependent Regulation of Endothelial Cell Morphology Revealed by Differential Functions of the FOXO Transcription Factors.

発表者；　松川　舞　氏
　　　（熊本大学　発生医学研究センター　造血発生分野）
Abstract；
　Foxo1 is a forkhead box transcription factor that is known to regulate metabolism, cellular proliferation and stress tolerance. However, Foxo1-null mice die around embryonic day 11 due to a remarkably impaired vascular development, suggesting a essential role of Foxo1 in vascular development. Previously, we reported that endothelial cells derived from Foxo1-null embryonic stem (ES) cells failed to elongate in response to exogenous vascular endothelial cell growth factor (VEGF) in culture. Recently, we found that the elongation of endothelial cells was also induced by transforming growth factor-β (TGF-β) in normal endothelial cells but not in Foxo1-null endothelial cells. These findings suggested that Foxo1-null endothelial cells have an impairment in morphological response to angiogenic stimuli, which might account for the failure of vascular development in nullizygous embryos. It has been reported that inactivation of neither the Foxo3a nor Foxo4 gene affected vascular development. In order to gain insight into the molecular basis of the function of Foxo1, we aimed to investigate whether other Foxo members were able to substitute for the functional role of Foxo1 in developing endothelial cells. We introduced Foxo3a transgene which is regulated by tet-off promoter into Foxo1-null ES cells. Induction of Foxo3a restored the elongation reaction of Foxo1-null endothelial cells in response to VEGF at a later differentiation stage but not early stage, indicating that Foxo3a is able to contribute to the morphological response of endothelial cells in a stage-dependent manner. Moreover, induction of either Foxo1 or Foxo3a at later stage gave rise to elongation of endothelial cells in response to even low concentration of VEGF which is secreted by stromal cells coexist in our culture system. These results suggest that endothelial cell morphology is regulated by several different mechanisms during the process of vascular development.