Presenilin-1 controls the growth and differentiation of endothelial progenitor cells through its beta-catenin-binding region.
Presenilin-1 (PS1) is a gene responsible for the development of early-onset familial Alzheimer's disease. Targeted disruption of the PS1 gene in mice suggested that PS1 might be involved in angiogenesis. We have used an in vitro embryonic stem (ES) cell culture system to prepare endothelial progenitor cells (EPC) lacking PS1 and investigated the roles of PS1 in endothelial cell lineage. With this system, Flk-1+ E-cadherin- EPC were generated from PS1-deficient ES cells, and the EPC lacking PS1 as well as wild-type EPC grew to form VE-cadherin+ endothelial colonies supported by a layer of OP9 stromal cells. Although the endothelial colonies from PS1-deficient EPC showed morphology similar to those from wild-type EPC, the PS1-deficient EPC formed a large number of the colonies compared to wild-type EPC. The enhanced colony-forming ability of PS1-deficient EPC was attenuated by the inductions of wild-type human PS1. To differentiate multiple activities of PS1 for colony-forming ability, we used two types of human PS1 mutants: one (hPS1D257A) with the aspartate to alanine mutation at residue 257 that impairs the proteolytic activity of PS1, and the other (hPS1Deltacat) deleting amino acids 340-371 of the cytosolic loop sequence essential for beta-catenin binding. hPS1D257A showed activity to regulate the colony-forming ability of PS1-deficient EPC, while hPS1Deltacat failed to exhibit this activity. These results suggest that PS1 regulates the growth and differentiation of endothelial progenitor cells through its beta-catenin-binding region and that the defect of PS1 function in endothelial cell lineage could contribute to the induction of vascular pathology.
Nakajima
Mitsunari
M
Department of Biosignal Research, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan. nakajima@tmig.or.jp
Ogawa
Minetaro
M
Shimoda
Yuri
Y
Hiraoka
Shuichi
S
Iida
Midori
M
Koseki
Haruhiko
H
Shirasawa
Takuji
T
Furukawa
Kiyoshi
K
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D053764:Presenilin-1; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051176:beta Catenin