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Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α

Nature Genetics volume 26, pages 379–382 (2000)Cite this article

Abstract

Phosphoinositide 3-kinases produce 3′-phosphorylated phosphoinositides that act as second messengers to recruit other signalling proteins to the membrane1. Pi3ks are activated by many extracellular stimuli and have been implicated in a variety of cellular responses1. The Pi3k gene family is complex and the physiological roles of different classes and isoforms are not clear. The gene Pik3r1 encodes three proteins (p85α, p55α and p50α) that serve as regulatory subunits of class IA Pi3ks (ref. 2). Mice lacking only the p85α isoform are viable but display hypoglycaemia and increased insulin sensitivity correlating with upregulation of the p55α and p50α variants3. Here we report that loss of all protein products of Pik3r1 results in perinatal lethality. We observed, among other abnormalities, extensive hepatocyte necrosis and chylous ascites. We also noted enlarged skeletal muscle fibres, brown fat necrosis and calcification of cardiac tissue. In liver and muscle, loss of the major regulatory isoform caused a great decrease in expression and activity of class IA Pi3k catalytic subunits; nevertheless, homozygous mice still displayed hypoglycaemia, lower insulin levels and increased glucose tolerance. Our findings reveal that p55α and/or p50α are required for survival, but not for development of hypoglycaemia, in mice lacking p85α.

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Figure 1: Histopathology in Pik3r1−/− mice.
Figure 2: Chylous ascites in a 3-day-old Pik3r1−/− mouse.
Figure 3: Lower glucose and insulin concentrations in Pik3r1−/− mice.
Figure 4: Biochemical analysis of Pi3k expression and activity in insulin-responsive tissues.

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Acknowledgements

We thank H. Warren and E. Meluleni for help with necropsy and histopathology; J. Alvarez for lipid analysis; M. White for the anti-p55γ antibody; T. Roberts for the anti-pTyr antibody; and I. Arias, S. Snapper, B. Sleckman, S. Thomas, M. Wahl and members of the Cantley and Kahn labs for helpful suggestions. D.A.F. was supported by fellowships from the Damon Runyan-Walter Winchell Cancer Research Fund and the Leukemia Society of America. This work was supported by NIH grants GM41890 to L.C.C. and DK55545 to C.R.K.

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Authors and Affiliations

  1. Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    David A. Fruman, Daniel A. Pollard, Claudine M. Yballe & Lewis C. Cantley

  2. Research Division, and Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    Franck Mauvais-Jarvis, Derek Brazil & C. Ronald Kahn

  3. Tufts School of Veterinary Medicine, Boston, Massachusetts, USA

    Roderick T. Bronson

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Correspondence to Lewis C. Cantley.

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Fruman, D., Mauvais-Jarvis, F., Pollard, D. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nat Genet 26, 379–382 (2000). https://doi.org/10.1038/81715

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