Ballard Mimmi S, Zhu Anna, Iwai Naomi, Stensrud Michael, Mapps Aurelia, Postiglione Maira Pia, Knoblich Juergen A, Hinck Lindsay
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Department of Biology, California State University Channel Islands, Camarillo, CA 93012, USA.
Cell Rep. 2015 Oct 13;13(2):290-301. doi: 10.1016/j.celrep.2015.09.006. Epub 2015 Oct 1.
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 causes more basal cap cells to divide 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.
组织稳态需要维持体细胞干细胞；然而，在器官发生过程中调节这一过程的机制尚未完全了解。在这里，我们在乳腺末端芽中鉴定出不对称更新的基底和腔干细胞。我们证明，SLIT2/ROBO1信号通路通过转录因子Snail（SNAI1）调控纺锤体定向机制的关键成员Inscuteable（mInsc），从而调节自我更新的不对称细胞分裂（ACD）和扩张性对称细胞分裂（SCD）之间的选择。SLIT2/ROBO1信号通路的缺失会增加细胞核中的SNAI1。SNAI1的过表达会增加mInsc的表达，而SLIT2处理可抑制这种效应。mInsc的增加不会改变乳腺（MG）中的细胞增殖，而是会导致更多的基底帽细胞通过SCD进行分裂，以ACD为代价，从而产生更多的干细胞和更大的生长物。总之，我们的研究深入了解了细胞外信号SLIT2如何调节乳腺干细胞的数量。
