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 processes. We have previously shown that mice deficient in alpha-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parietal cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibin-deficient mice secrete high levels of activins. In addition, Northern blot analysis has localized activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced activins act through ActRII to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of activin signaling through ActRII in vivo, we generated compound homozygous mutant mice deficient in both alpha-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of activin signaling through ActRII in hepatocytes and the glandular stomach causes the hepatocellular necrosis and depletion of parietal cells in the glandular stomach as well as the severe weight loss in vivo.
Coerver
K A
KA
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Woodruff
T K
TK
Finegold
M J
MJ
Mather
J
J
Bradley
A
A
Matzuk
M M
MM
D029404:Activin Receptors; D028341:Activins; D000818:Animals; D002100:Cachexia / Q000209:etiology*; D005260:Female; D007265:Inhibins / Q000172:deficiency* / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009842:Oligopeptides; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000502:physiology*; D018312:Sex Cord-Gonadal Stromal Tumors / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology; D013736:Testicular Neoplasms / Q000378:metabolism / Q000473:pathology; D015431:Weight Loss
D009842:Oligopeptides; D010455:Peptides; D017978:Receptors, Growth Factor; C044147:activin B; D028341:Activins; C048617:myelopeptides; D007265:Inhibins; D029404:Activin Receptors