Essential role of PDK1 in regulating cell size and development in mice.
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 approximately 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.
Lawlor
Margaret A
MA
MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK. m.a.lawlor@dundee.ac.uk
Mora
Alfonso
A
Ashby
Peter R
PR
Williams
Michayla R
MR
Murray-Tait
Victoria
V
Malone
Lorraine
L
Prescott
Alan R
AR
Lucocq
John M
JM
Alessi
Dario R
DR
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001483:Base Sequence; D048429:Cell Size / Q000502:physiology*; D017931:DNA Primers; D004622:Embryo, Mammalian / Q000378:metabolism / Q000648:ultrastructure; D005314:Embryonic and Fetal Development / Q000502:physiology*; D004789:Enzyme Activation; D005804:Genes, Lethal; D051379:Mice; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases