TY - JOUR
T1 - Krüppel-like factor 5 Is Essential for Blastocyst Development and the Normal Self-Renewal of Mouse ESCs
AU - Ema, Masatsugu
AU - Mori, Daisuke
AU - Niwa, Hitoshi
AU - Hasegawa, Yoshikazu
AU - Yamanaka, Yojiro
AU - Hitoshi, Seiji
AU - Mimura, Junsei
AU - Kawabe, Yoh ichi
AU - Hosoya, Tomohiro
AU - Morita, Masanobu
AU - Shimosato, Daisuke
AU - Uchida, Kazuhiko
AU - Suzuki, Norio
AU - Yanagisawa, Jun
AU - Sogawa, Kazuhiro
AU - Rossant, Janet
AU - Yamamoto, Masayuki
AU - Takahashi, Satoru
AU - Fujii-Kuriyama, Yoshiaki
N1 - Funding Information:
We thank Drs. Satoshi Tanaka, Junko Tomizawa, Satoshi Ohtsuka, Yoshihiro Miwa, Junko Tanaka, Eiji Hara, and Noriko Gotoh for helpful discussion and reagents and Dr. Shinya Yamanaka and Masafumi Onodera for providing us with plasmids and GFP retrovirus. M.E. thanks Ms. Yuko Suzuki and Masami Ojima for technical assistance. M.E. thanks Drs. Amy Ralston and Vincent P. Kelly for critical reading of the manuscript K.U. thanks Makoto Asashima and members of CBIRI at Organ Development Research Laboratory, AIST for valuable discussion. This work was supported in part by a grant from CREST, Japan Science Technology (Y.F.-K), and a Grant-in-Aid for Scientific Research on Priority Areas (17045004, 20052008) (M.E.). M.E. and D.M. contributed equally to this work. M.E., D.M., J.M., Y.K., K.K., Y.H., K.U., and J.Y. performed biochemical and cell biological experiments. N.H. and D.S. performed blastocyst injections after LIF-free culture of Klf5-overexpressing ESCs. K.U. performed microarray analysis. D.S., T.H., M.M., and N.S. performed mouse experiments. Y.Y. contributed to confocal imaging. M.E., H.N., Y.Y., J.R., S.T., M.Y., and Y.F-K. contributed to hypothesis development, experimental design, and data interpretation. M.E. wrote the paper.
PY - 2008/11/6
Y1 - 2008/11/6
N2 - The transcription factor Klf4 has demonstrated activity in the reprogramming of somatic cells to a pluripotent state, but the molecular mechanism of this process remains unknown. It is, therefore, of great interest to understand the functional role of Klf4 and related genes in ESC regulation. Here, we show that homozygous disruption of Klf5 results in the failure of ESC derivation from ICM cells and early embryonic lethality due to an implantation defect. Klf5 KO ESCs show increased expression of several differentiation marker genes and frequent, spontaneous differentiation. Conversely, overexpression of Klf5 in ESCs suppressed the expression of differentiation marker genes and maintained pluripotency in the absence of LIF. Our results also suggest that Klf5 regulates ESC proliferation by promoting phosphorylation of Akt1 via induction of Tcl1. These results, therefore, provide new insights into the functional and mechanistic role of Klf5 in regulation of pluripotency.
AB - The transcription factor Klf4 has demonstrated activity in the reprogramming of somatic cells to a pluripotent state, but the molecular mechanism of this process remains unknown. It is, therefore, of great interest to understand the functional role of Klf4 and related genes in ESC regulation. Here, we show that homozygous disruption of Klf5 results in the failure of ESC derivation from ICM cells and early embryonic lethality due to an implantation defect. Klf5 KO ESCs show increased expression of several differentiation marker genes and frequent, spontaneous differentiation. Conversely, overexpression of Klf5 in ESCs suppressed the expression of differentiation marker genes and maintained pluripotency in the absence of LIF. Our results also suggest that Klf5 regulates ESC proliferation by promoting phosphorylation of Akt1 via induction of Tcl1. These results, therefore, provide new insights into the functional and mechanistic role of Klf5 in regulation of pluripotency.
KW - STEMCELL
UR - http://www.scopus.com/inward/record.url?scp=54949147295&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54949147295&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2008.09.003
DO - 10.1016/j.stem.2008.09.003
M3 - Article
C2 - 18983969
AN - SCOPUS:54949147295
SN - 1934-5909
VL - 3
SP - 555
EP - 567
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 5
ER -