TY - JOUR
T1 - Essential role of PDK1 in regulating cell size and development in mice
AU - Lawlor, Margaret A.
AU - Mora, Alfonso
AU - Ashby, Peter R.
AU - Williams, Michayla R.
AU - Murray-Tait, Victoria
AU - Malone, Lorraine
AU - Prescott, Alan R.
AU - Lucocq, John M.
AU - Alessi, Dario R.
PY - 2002/7/15
Y1 - 2002/7/15
N2 - PDK1 functions as a master kinase, phosphorylating and activating PKB/Akt, S6K and RSK. To learn more about the roles of PDK1, we generated mice that either lack PDK1 or possess PDK1 hypomorphic alleles, expressing only ∼10% of the normal level of PDK1. PDK1-/- embryos die at embryonic day 9.5, displaying multiple abnormalities including lack of somites, forebrain and neural crest derived tissues; however, development of hind- and midbrain proceed relatively normally. In contrast, hypomorphic PDK1 mice are viable and fertile, and insulin injection induces the normal activation of PKB, S6K and RSK. Nevertheless, these mice are 40-50% smaller than control animals. The organ volumes from the PDK1 hypomorphic mice are reduced proportionately. We also establish that the volume of a number of PDK1-deficient cells is reduced by 35-60%, and show that PDK1 deficiency does not affect cell number, nuclear size or proliferation. We provide genetic evidence that PDK1 is essential for mouse embryonic development, and regulates cell size independently of cell number or proliferation, as well as insulin's ability to activate PKB, S6K and RSK.
AB - PDK1 functions as a master kinase, phosphorylating and activating PKB/Akt, S6K and RSK. To learn more about the roles of PDK1, we generated mice that either lack PDK1 or possess PDK1 hypomorphic alleles, expressing only ∼10% of the normal level of PDK1. PDK1-/- embryos die at embryonic day 9.5, displaying multiple abnormalities including lack of somites, forebrain and neural crest derived tissues; however, development of hind- and midbrain proceed relatively normally. In contrast, hypomorphic PDK1 mice are viable and fertile, and insulin injection induces the normal activation of PKB, S6K and RSK. Nevertheless, these mice are 40-50% smaller than control animals. The organ volumes from the PDK1 hypomorphic mice are reduced proportionately. We also establish that the volume of a number of PDK1-deficient cells is reduced by 35-60%, and show that PDK1 deficiency does not affect cell number, nuclear size or proliferation. We provide genetic evidence that PDK1 is essential for mouse embryonic development, and regulates cell size independently of cell number or proliferation, as well as insulin's ability to activate PKB, S6K and RSK.
KW - Cell growth
KW - Cell size
KW - Embryonic development
KW - PDK1
KW - PI 3-kinase
KW - PKB-Akt
UR - http://www.scopus.com/inward/record.url?scp=0037099658&partnerID=8YFLogxK
U2 - 10.1093/emboj/cdf387
DO - 10.1093/emboj/cdf387
M3 - Article
C2 - 12110585
AN - SCOPUS:0037099658
VL - 21
SP - 3728
EP - 3738
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 14
ER -