Coerver K A, Woodruff T K, Finegold M J, Mather J, Bradley A, Matzuk M M
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Endocrinol. 1996 May;10(5):534-43. doi: 10.1210/mend.10.5.8732684.
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.
激活素和抑制素是转化生长因子-β超家族的成员，参与多种生理和发育过程。我们之前已经表明，α-抑制素缺陷的小鼠在幼年时会发生性腺性索间质肿瘤。肿瘤发生后很快会出现消瘦综合征，包括严重体重减轻、中央静脉周围肝细胞坏死以及腺胃壁细胞减少。抑制素缺陷小鼠的肝脏组织学与用重组激活素A对大鼠和小鼠进行短期治疗的病理效应相似。与这些发现一致，我们已经表明抑制素缺陷小鼠的性腺肿瘤分泌高水平的激活素。此外，Northern印迹分析已将II型激活素受体（ActRII）定位到肝脏。基于这些研究，我们推测肿瘤产生的激活素通过ActRII起作用，导致抑制素缺陷小鼠出现消瘦综合征。为了验证这一假设并确定体内通过ActRII的激活素信号水平升高的意义，我们生成了同时缺乏α-抑制素和ActRII的复合纯合突变小鼠。尽管性腺性索间质肿瘤持续发展且血清中激活素A和B水平升高，但复合纯合突变小鼠没有出现异常体重减轻，并且大多数小鼠的胃和肝脏在组织学上是正常的。这些结果表明，肝细胞和腺胃中通过ActRII的激活素信号水平升高会导致体内肝细胞坏死、腺胃壁细胞减少以及严重体重减轻。
