Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha

Phosphoinositide 3-kinases produce 3'-phosphorylated phosphoinositides that act as second messengers to recruit other signalling proteins to the membr ane(1). Pi3ks are activated by many extracellular stimuli and have been imp licated in a variety of cellular responses(1). The Pi3k gene family is comp lex and the physiological roles of different classes and isoforms are not c lear. The gene Pik3r1 encodes three proteins (p85 alpha, p55 alpha and p50 alpha) that serve as regulatory subunits of class I-A Pi3ks (ref. 2). Mice lacking only the p85a isoform are viable but display hypoglycaemia and incr eased insulin sensitivity correlating with upregulation of the p55 alpha an d p50 alpha variants(3). Here we report that loss of all protein products o f Pik3r1 results in perinatal lethality. We observed, among other abnormali ties, extensive hepatocyte necrosis and chylous ascites, We also noted enla rged skeletal muscle fibres, brown fat necrosis and calcification of cardia c tissue. In liver and muscle, loss of the major regulatory isoform caused a great decrease in expression and activity of class I-A Pi3k catalytic sub units: nevertheless, homozygous mice still displayed hypoglycaemia, lower i nsulin levels and increased glucose tolerance. Our findings reveal that p55 alpha and/or p50 alpha are required for survival, but not for development of hypoglycaemia, in mice lacking p85 alpha.