BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms
BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms
复制标题
DOI：
10.1016/j.devcel.2006.12.003
复制
发表时间：
2007-02-01
影响因子：
11.8
通讯作者：
Brugge, Joan S.
中科院分区：
文献类型：
--
作者：
Mailleux, Arnaud A.;Overholtzer, Michael;Brugge, Joan S.
成年未生育的乳腺是一种高度有序的树状结构，由具有中空管腔的导管构成。尽管青春期发育过程中的管腔形成似乎涉及细胞凋亡，但调节这一过程的分子机制尚不清楚。在此，我们证明在小鼠中破坏仅含BH3结构域的促凋亡因子Bim可阻止青春期末梢终芽中细胞凋亡的诱导以及管腔的清除。然而，填充假定管腔空间的细胞最终会通过一种不依赖半胱天冬酶的死亡过程从相邻导管中被清除。在充满细胞的Bim（-/-）导管内，上皮细胞在清除之前会失去基质附着并发生鳞状分化。同样，当永生化的乳腺上皮细胞从基质上脱离时，我们在体外也检测到鳞状分化。这些数据为塑造乳腺所涉及的过程提供了重要的机制信息，并证明BIM是体内细胞凋亡的关键调节因子。
The adult, virgin mammary gland is a highly organized tree-like structure formed by ducts with hollowed lumen. Although lumen formation during pubertal development appears to involve apoptosis, the molecular mechanisms that regulate this process are not known. Here, we demonstrate that disruption of the BH3-only proapoptotic factor Bim in mice prevents induction of apoptosis in and clearing of the lumen in terminal end buds during puberty. However, cells that fill the presumptive luminal space are eventually cleared from the adjacent ducts by a caspase-independent death process. Within the filled Bim(-/-) ducts, epithelial cells are deprived of matrix attachment and undergo squamous differentiation prior to clearing. Similarly, we also detect squamous differentiation in vitro when immortalized mammary epithelial cells are detached from the matrix. These data provide important mechanistic information on the processes involved in sculpting the mammary gland and demonstrate that BIM is a critical regulator of apoptosis in vivo.