Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence
Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence
复制标题
DOI：
10.1016/j.devcel.2018.10.001
复制
发表时间：
2018-12-03
影响因子：
11.8
通讯作者：
Visvader, Jane E.
中科院分区：
文献类型：
--
作者：
Fu, Nai Yang;Pal, Bhupinder;Visvader, Jane E.
长寿命的静止乳腺干细胞（MaSCs）被认为是协调发生在出生后发育的不同阶段的导管上皮细胞的急剧扩张，但对支持其激活的分子调节因子知之甚少。我们发现，消融的转录因子Foxp1在乳腺深刻损害导管形态发生，导致在整个生命的一个基本的树。Foxp1缺陷的腺体高度富集静止的Tspan8（hi）MaSCs，其甚至在竞争性移植测定中也未能被激活，因此突出了细胞内在缺陷。Foxp1缺失也导致管腔细胞中基础基因的异常表达，推断在细胞命运决定中的作用。值得注意的是，Foxp1被发现是基底细胞中Tspan8的直接阻遏物，Tspan8的缺失挽救了Foxp1缺失引起的导管形态发生缺陷。因此，单个转录调节因子Foxp1可以控制MaSCs从休眠退出以协调分化和发育。
Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1-deficient glands were highly enriched for quiescent Tspan8(hi) MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect. Foxp1 deletion also resulted in aberrant expression of basal genes in luminal cells, inferring a role in cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of Tspan8 in basal cells, and deletion of Tspan8 rescued the defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator Foxp1 can control the exit of MaSCs from dormancy to orchestrate differentiation and development.