Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris 75005, France ; INSERM U1024, Paris 75005, France ; CNRS UMR 8197, Paris 75005, France.
Stem Cell Reports. 2014 Apr 3;2(4):491-506. doi: 10.1016/j.stemcr.2014.02.011. eCollection 2014 Apr 8.
Little is known about the mechanisms of mitotic spindle orientation during mammary gland morphogenesis. Here, we report the presence of huntingtin, the protein mutated in Huntington's disease, in mouse mammary basal and luminal cells throughout mammogenesis. Keratin 5-driven depletion of huntingtin results in a decreased pool and specification of basal and luminal progenitors, and altered mammary morphogenesis. Analysis of mitosis in huntingtin-depleted basal progenitors reveals mitotic spindle misorientation. In mammary cell culture, huntingtin regulates spindle orientation in a dynein-dependent manner. Huntingtin is targeted to spindle poles through its interaction with dynein and promotes the accumulation of NUMA and LGN. Huntingtin is also essential for the cortical localization of dynein, dynactin, NUMA, and LGN by regulating their kinesin 1-dependent trafficking along astral microtubules. We thus suggest that huntingtin is a component of the pathway regulating the orientation of mammary stem cell division, with potential implications for their self-renewal and differentiation properties.
关于有丝分裂纺锤体在乳腺形态发生过程中的定向机制知之甚少。在这里，我们报告亨廷顿病突变蛋白亨廷顿在整个乳腺发生过程中存在于小鼠乳腺基底和腔细胞中。角蛋白 5 驱动的亨廷顿的耗竭导致基底和腔祖细胞的池减少和规范，并改变乳腺形态发生。对耗尽亨廷顿的基底祖细胞中的有丝分裂的分析显示有丝分裂纺锤体定向错误。在乳腺细胞培养中，亨廷顿通过与动力蛋白的相互作用以动力蛋白依赖的方式调节纺锤体取向。亨廷顿通过调节沿星体微管的依赖驱动蛋白的运输，靶向于纺锤体极，促进 NUMA 和 LGN 的积累。亨廷顿对于动力蛋白、动力蛋白复合体、NUMA 和 LGN 的皮质定位也是必不可少的，通过调节它们沿星体微管的依赖驱动蛋白的运输。因此，我们认为亨廷顿是调节乳腺干细胞分裂方向的途径的一个组成部分，这可能对它们的自我更新和分化特性有影响。
