ACTIVIN SIGNALING THROUGH ACTIVIN RECEPTOR TYPE-II CAUSES THE CACHEXIA-LIKE SYMPTOMS IN INHIBIN-DEFICIENT MICE

Activins and inhibins, members of the transforming growth factor-beta superfamily, are involved in diverse physiological and developmental p rocesses. We have previously shown that mice deficient in alpha-inhibi n develop gonadal sex cord-stromal tumors at an early age. The tumor d evelopment is rapidly followed by a wasting syndrome that includes sev ere weight loss, hepatocellular necrosis around the central vein, and depletion of the parietal cells in the glandular stomach. The liver hi stology in inhibin-deficient mice is similar to the pathological effec ts of short-term treatment of rats and mice with recombinant activin A . Consistent with these findings, we have shown that the gonadal tumor s in the inhibin-deficient mice secrete high levels of activins. In ad dition, Northern blot analysis has localized activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumo r-produced activins act through ActRII to cause the wasting syndrome i n inhibin-deficient mice. To test this hypothesis and determine the si gnificance of elevated levels of activin signaling through ActRII in v ivo, we generated compound homozygous mutant mice deficient in both al pha-inhibin and ActRII. Despite the continued development of gonadal s ex cord-stromal tumors and elevated serum levels of activin A and B, t he compound homozygous mutant mice suffered no unusual weight loss, an d the stomachs and livers of the majority of the mice were histologica lly normal. These results demonstrate that increased levels of activin signaling through ActRII in hepatocytes and the glandular stomach cau ses the hepatocellular necrosis and depletion of parietal cells in the glandular stomach as well as the severe weight loss in vivo.