Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC.
Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC.
复制标题
乳细胞自我更新受SNAI1和MINSC信号传导调节。
DOI：
10.1016/j.celrep.2015.09.006
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发表时间：
2015-10-13
期刊：
影响因子：
8.8
通讯作者：
Hinck L
中科院分区：
文献类型：
--
作者：
Ballard MS;Zhu A;Iwai N;Stensrud M;Mapps A;Postiglione MP;Knoblich JA;Hinck L
组织动态平衡需要躯体干细胞的维持；然而，在器官发生过程中调节这一过程的机制还不是很清楚。在这里，我们确定了不对称更新的基础和腔干细胞在乳房末端芽。我们证明，Slit2/Robo1信号通过转录因子Snail(SNAI1)调控纺锤体定向机制的关键成员不可切(MInsc)，从而调节自我更新的不对称细胞分裂(ACDs)和扩张性对称细胞分裂(SCD)之间的选择。Slit2/Robo1信号的丢失增加了细胞核中的SNAI1。过表达SNAI1可增加mInsc的表达，这种作用可被Slit2抑制。MInsc的增加不会改变乳腺(MG)的细胞增殖，相反会导致更多的基帽细胞通过SCD分裂，而ACD的代价是更多的干细胞和更大的突起。总之，我们的研究为乳腺干细胞的数量如何受到细胞外信号SLIT2的调节提供了洞察力。
Tissue homeostasis requires somatic stem cell maintenance; however, mechanisms regulating this process during organogenesis are not well understood. Here, we identify asymmetrically renewing basal and luminal stem cells in the mammary end bud. We demonstrate that SLIT2/ROBO1 signaling regulates the choice between self-renewing asymmetric cell divisions (ACDs) and expansive symmetric cell divisions (SCDs) by governing Inscuteable (mInsc), a key member of the spindle orientation machinery, through the transcription factor Snail (SNAI1). Loss of SLIT2/ROBO1 signaling increases SNAI1 in the nucleus. Overexpression of SNAI1 increases mInsc expression, an effect that is inhibited by SLIT2 treatment. Increased mInsc does not change cell proliferation in the mammary gland (MG), but instead results in more basal cap cells dividing via SCD, at the expense of ACD, leading to more stem cells and larger outgrowths. Together, our studies provide insight into how the number of mammary stem cells is regulated by the extracellular cue, SLIT2.