PO-187 Defective liver regeneration ability of Sos1-KO and Sos1/2-dKO, but not Sos2-KO mice

IntroductionTo ascertain specific functional role(s) of the Sos1 and Sos2 Ras-GEF activators we investigated phenotypic effects of single or combined disruption of Sos1 and/or Sos2 in adult mice by using a tamoxifen-inducible Sos1-KO system. Upon TAM induction, the resulting Sos1/2-DKO animals die precipitously (in about 2 weeks) whereas single Sos1-KO or Sos2-KO adult mice are perfectly viable. Histological examination of DKO mice showed that the internal organs most severely affected by concomitant Sos1 and Sos2 loss include the liver and gallbladder in the gastrointestinal (GI) tract.Material and methodsTo determine cause(s) of the quick death of Sos1/2-DKO mice, we analysed blood and GI tissues from 6–8 week-old mice of 4 relevant Sos genotypes (WT, Sos1-KO, Sos2-KO and Sos1/2-DKO) similarly treated with TAM for 13 days. Different biochemical parameters were quantitated in blood serum and liver samples, and various IHC assays were also performed on different organs of the GI tract. Liver regeneration was characterised by means of partial hepatectomy studies of WT, Sos1-KO and Sos2-KO animals previously treated with TAM for 10 days.Results and discussionsCombined loss of Sos1 and Sos2 in DKO mice resulted in markedly reduced levels of total serum protein and increased serum levels of lactate dehydrogenase, creatinine kinase and other liver enzymes, suggesting the occurrence of substantial liver failure in these animals. Histological analysis of the DKO animals showed a quick overall structural degeneration of the liver accompanied by increased levels of oxidative stress in the hepatic lobules. We also observed marked distension of the gallbladder, perhaps linked to decreased CCK levels in the gut mucosa cells. The dilatation of the gallbladder together with the observed decrease of serum triglycerides and fat in all the organs analysed point to significant impairment of the lipidic metabolism in Sos1/2-DKO mice. Finally, our partial hepatectomy studies in single Sos KO mice showed that hepatic regeneration critically depends on the presence of Sos1, whereas Sos2 appears to be dispensable for this process of organ recovery after liver damage.ConclusionOur data suggest functional redundancy of Sos1 and Sos2 for overall homeostasis of GI organs, especially liver and gallbladder. Our studies also show that Sos1, but not Sos2, is the main, critical RasGEF required for liver regeneration and tissue repair upon organ injury.Supported by AECC, PI16/0213, PI19/0