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Essential role of PDK1 in regulating cell size and development in mice
Author(s) -
Lawlor Margaret A.,
Mora Alfonso,
Ashby Peter R.,
Williams Michayla R.,
MurrayTait Victoria,
Malone Lorraine,
Prescott Alan R.,
Lucocq John M.,
Alessi Dario R.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf387
Subject(s) - biology , p70 s6 kinase 1 , protein kinase b , neural crest , microbiology and biotechnology , forebrain , tor signaling , cell growth , embryonic stem cell , insulin , embryo , phosphorylation , signal transduction , endocrinology , medicine , genetics , gene , central nervous system
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.