Title:
Forkhead transcriptional factor 1 (Foxo1) regulates vascular endothelial cell morphology

Tamura Kiyomi ( Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University )

Abstract:
Foxo1-deficient mice die around embryonic day 11 due to failure of the development of branchial arches and abnormal vascular development of embryos and yolk sacs (Furuyama et.al. J Biol Chem., vol. 279, p34741-34749, 2004). These findings suggested that Foxo1 regulate the organization of vascular system in embryogenesis . However, the mechanism is largely unknown.
In previous studies , we used a three-dimensional culture system for vascular endothelial cells (EC) and vascular smooth muscle cells (SMC) derived from mouse ES cells. Foxo1 (+/+) EC showed spindle-shaped elongation and EC-SMC binding. On the other hand, Foxo1 (-/-) EC failed to elongate and interacte with SMC ( BBRC, vol. 390, p861-866, 2009 , Embryonic Stem Cells, chapter 30, p581-606, 2011).
To gain specific factors into the mechanism of EC regulation by Foxo1, we used DNA microarray. Several genes show the decreased mRNA expression in Foxo1 (-/-) EC.
We picked up these genes as candidate factors of Foxo1 targets. Foxo1 (-/-) EC derived from ES cells transfected with each candidate factors were cultured in the present of vascular endothelial growth factor (VEGF) and were examined whether the candidate factors rescued EC elongation.
Finally , Foxo1 (-/-) EC transfected with protein phosphatase 1, regulatory (inhibitor) subunit 14C ( PPP1R14C) showed EC elongation. Protein phosphatase-1 (PP1) is known to regulate cell morphology. PPP1R14C is an inhibitor of PP1. The molecular details of the interaction of PPP1R14C with Foxo1 in vascular developing are unclear. I discuss the previous findings about factors regulating EC morphology.