Yokouchi Y, Sakiyama J, Kameda T, Iba H, Suzuki A, Ueno N, Kuroiwa A
Department of Molecular Biology, School of Science, Nagoya University, Furo-cho, Chikusa-ku, Japan.
Development. 1996 Dec;122(12):3725-34. doi: 10.1242/dev.122.12.3725.
During limb development, the mesenchymal cells in restricted areas of limb bud, anterior necrotic zone, posterior necrotic zone, opaque zone and interdigital necrotic zones, are eliminated by programmed cell death. The transcripts of bone morphogenetic protein (Bmp)-2 and -4 were first detected in the areas where cell death was observed, then showed overlapping expression with the programmed cell death zones except the opaque zone. To investigate the function of BMP-2 and BMP-4 during limb pattern formation, the dominant negative form of BMP receptor was overexpressed in chick leg bud via a replication-competent retrovirus to block the endogenous BMP-2/-4 signaling pathway. This resulted in excess web formation at the anterior and posterior regions of limb buds in addition to marked suppression of the regression of webbing at the interdigital regions. Significant reductions in the number of apoptotic cells in these three necrotic zones were found in the limb buds which received the virus carrying dominant negative BMP receptor. This indicates that extra tissue formation is due to suppression of programmed cell death in the three necrotic zones. Moreover, BMP-2/-4 protein induced apoptosis of mesenchymal cells isolated from the interdigital region in vitro. Other TGFbeta family proteins as TGFbeta1 and Activin did not show this effect. These results suggest that BMP-2 and BMP-4 are the apoptotic signal molecules of the programmed cell death process in the chick limb buds.
在肢体发育过程中，肢体芽的特定区域、前坏死区、后坏死区、不透明区和指间坏死区的间充质细胞通过程序性细胞死亡被清除。骨形态发生蛋白（Bmp）-2和-4的转录本首先在观察到细胞死亡的区域被检测到，然后除不透明区外，在程序性细胞死亡区域呈重叠表达。为了研究BMP-2和BMP-4在肢体模式形成过程中的功能，通过有复制能力的逆转录病毒在鸡胚腿芽中过表达BMP受体的显性负性形式，以阻断内源性BMP-2/-4信号通路。这导致肢体芽的前部和后部区域出现过多的蹼形成，同时指间区域的蹼退化明显受到抑制。在接受携带显性负性BMP受体病毒的肢体芽中，发现这三个坏死区的凋亡细胞数量显著减少。这表明额外组织的形成是由于这三个坏死区的程序性细胞死亡受到抑制。此外，BMP-2/-4蛋白在体外可诱导从指间区域分离的间充质细胞凋亡。其他TGFβ家族蛋白如TGFβ1和激活素则没有这种作用。这些结果表明，BMP-2和BMP-4是鸡胚肢体芽程序性细胞死亡过程中的凋亡信号分子。
