不对称的细胞分裂促进表皮分化缺口依赖.doc
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1、不对称的细胞分裂促进表皮分化缺口依赖 Scott E. Williams, Slobodan Beronja, H. Amalia Pasolli, and Elaine Fuchs 1 ,H.阿玛利亚Pasolli,Beronja斯洛博丹斯科特E.威廉姆斯,和伊莱恩福克斯1 Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University, New York, New York 10065, USA.霍华德休斯医学研究所,实验室,哺乳动
2、物细胞生物学与发展,洛克菲勒大学,纽约,纽约10065,USA。 Elaine Fuchs: fuchslbrockefeller.edu 伊莱恩的福克斯fuchslbrockefeller.edu 1 To whom correspondence should be addressed: Elaine Fuchs, Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University, 1230 York Avenue, Box 300,
3、New York, NY, 10065, USA. 1谁信件应该得到解决:伊莱恩福克斯,霍华德休斯医学研究所,实验室,哺乳动物细胞生物学与发展,洛克菲勒大学,1230纽约大街300箱,纽约,NY,10065,USA。 Phone: 212-327-7953, Fax: 212-327-7954,电话:212-327-7953,传真:212-327-7954, Email: fuchslbrockefeller.edu 电子邮件fuchslbrockefeller.edu fuchslbrockefeller.edu Users may view, print, copy, download a
4、nd text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http:/ http:/ / license.html中条款 The publishers final edited version of this article is available at Nature出版商的最终编辑版本的这篇文章是在自然 See other articles in PMC that cite
5、 the published article.参见其他文章PMC 引用发表的文章。 Other Sections 第 o Summary 总结 o Introduction 介绍 o Results 结果 o Discussion 讨论 o Methods Summary 方法总结 o Methods 方法 o Supplementary Material 补充材料 o References 参考文献 Summary总结 Stem and progenitor cells utilize asymmetric cell divisions to balance proliferation an
6、d differentiation.干细胞和祖细胞利用非对称细胞分裂,到平衡的增殖和分化。 Evidence from lower eukaryotes shows that this process is regulated by proteins asymmetrically distributed at the cell cortex during mitosis: (1) Par3-Par6-aPKC, conferring polarity; (2) Gi-LGN/AGS3-NuMA-p150 glued , governing spindle positioning.从低等真核生物
7、的证据表明,这个过程是受非对称分布的蛋白质在细胞皮层,在有丝分裂过程中:(1)Par3的PAR6 aPKC,赋予极性(2)Gi-LGN/AGS3-NuMA-p150 粘 ,执政主轴定位。 Here, we focus on developing mouse skin, where progenitors execute a switch from predominantly symmetric to asymmetric divisions concomitant with stratification.在这里,我们专注于发育中的小鼠皮肤,祖细胞执行开关主要是对称的,不对称分裂伴随着分层。 U
8、sing in vivo skin-specific lentiviral RNAi, we investigate spindle orientation regulation and provide direct evidence that LGN, Numa1 and Dctn1 are involved.使用在特定的活体皮肤的慢病毒RNA干扰,我们研究主轴方向调节,并提供直接的证据表明,LGN,Numa1和Dctn1参与。 In compromising asymmetric cell divisions, we uncover profound defects in stratifi
9、cation, differentiation and barrier formation, and implicate Notch signalling as an important effector.在损害非对称细胞分裂时,我们发现深刻的缺陷形成分层,分化和障碍,并牵连Notch信号通路作为一个重要的效应。 Our study demonstrates the efficacy of applying RNAi in vivo to mammalian systems, and the ease of uncovering complex genetic interactions, he
10、re to gain insights into how changes in spindle orientation are coupled to establishing proper tissue architecture during skin development.我们的研究表明,在体内哺乳动物系统中的应用RNAi效果,揭示复杂的遗传相互作用,深入了解如何变化,主轴定向耦合到皮肤的发育过程中建立适当的组织架构和易用性。 Other Sections 第 o Summary 总结 o Introduction 介绍 o Results 结果 o Discussion 讨论 o Met
11、hods Summary 方法总结 o Methods 方法 o Supplementary Material 补充材料 o References 参考文献 Introduction介绍 Asymmetric cell divisions (ACDs) are important regulators of stem cell and cancer biology. 1 The genetic pathways underlying spindle orientation and ACDs have been best studied in C.非对称细胞分裂(ACDS)的重要调节干细胞和癌症
12、生物学的遗传途径已基本主轴定向和ACD最好的研究方法C. elegans and Drosophila , where conserved sets of proteins are asymmetrically distributed at the cell cortex during mitosis: the Par complexconsisting of Bazooka(Par3), Par6 and atypical protein kinase C(aPKC)functions as a master polarity determinant, while Gi, Pins(LGN/
13、AGS3), Mud(NuMA) and p150 glued (Dctn1), regulate spindle positioning. 2 , 3 In Drosophila neuroblasts, Inscuteable links these complexes by binding to both Par3 and Pins. 4 6 As neuroblasts progress through mitosis, Insc/Pins/Mud polarize and segregate into one daughter, retaining its progenitor st
14、atus, while the other daughter inherits oppositely polarized proteins including the Notch inhibitor Numb, which promotes differentiation. 2 , 3 线虫和果蝇中 ,保守的蛋白质组非对称地分布在皮质细胞在有丝分裂过程中:帕复杂的火箭筒(Par3的),PAR6和非典型蛋白激酶C(aPKC)作为主极性的决定因素,而Gi,的引脚(LGN/AGS3),泥(NUMA)和P150 粘 (Dctn1),调节主轴定位。 2 ,在果蝇神经母,Inscuteable的链接这些复
15、合物结合,Par3的和销。 4 - 6进步作为神经母细胞有丝分裂, INSC /销/泥分化和隔离成一个女儿,保留它的祖先状态,而另一个女儿继承的Notch抑制剂麻木,促进分化的极性相反的蛋白质。 2 , 3 ACDs have also been documented in vertebrates, including in mouse skin, where a shift from predominantly parallel/symmetric to perpendicular/asymmetric divisions occurs at embryonic day (E)14 coin
16、cident with stratification. 7 9 Basal delamination has been implicated in the process, and although ACDs could be critical, 10 direct functional evidence is lacking to support or refute a role for ACDs in promoting tissue growth and architecture for this or any other mammalian system. ACDS也被记录在脊椎动物中
17、,包括在小鼠皮肤的转变,从主要对称的并行/垂直/不对称分裂发生在胚胎天(E)14与分层相一致。 7 - 9基底分层有牵连的过程中, ,虽然ACDS是至关重要的,直接功能证据不足,ACDS促进组织的生长和体系结构或任何其他哺乳动物的系统来支持或反驳的作用。 As in lower eukaryotes, ACD components polarize in mitotic basal keratinocytes, forming an apical crescent of LGN and an interacting partner, NuMA. 7 , 11 13 NuMA in turn b
18、inds microtubules and cytoplasmic dynein, partially colocalising with the p150 glued /Dctn1 dynein-dynactin component in cultured keratinocytes. 7 LGN is thought to be recruited to the cell cortex through GPI-linked Gi/Go, which binds LGNs C-terminal GoLoco motifs.在低等真核生物,ACD组件极化基底角质形成细胞在有丝分裂,形成根尖月牙
19、LGN和相互作用的伙伴,NuMA的。 7 , 11 - 13的NuMA反过来结合微管和胞质动力蛋白,部分colocalising与P150 胶合 / Dctn1的动力蛋白dynactin组成部分,在培养的角质形成细胞。 7 LGN被认为是招募到的细胞皮层通过GPI连接Gi/Go的,结合LGN的C-末端GoLoco的图案。 Such interactions likely reorient the mitotic spindle through cortical capture of astral microtubules. 14 18这种相互作用可能重新调整的有丝分裂纺锤体通过皮质捕捉星体微管
20、。 14 - 18 To explore the physiological relevance of the LGN/NuMA/Dctn1 pathway, we devised a strategy to efficiently knockdown its constituents at a time during skin development when divisions become primarily asymmetric.为了探索的生理相关的LGN/NuMA/Dctn1途径,我们设计了一项战略,以有效地击倒它的成分在皮肤的发育过程中,当部门成为主要不对称。 Our method
21、 employs ultrasound-mediated delivery of high-titre lentivirus into amniotic space. 19 Lentivirus selectively transduces the first cell layer it encounters, which shortly after gastrulation is single-layered epidermis.我们的方法采用超声高滴度的慢病毒载体介导的交付到羊水空间19慢病毒选择性地转导在第一电池层,它遇到,不久后原肠胚是单层表皮。 Avoiding tissue-spe
22、cific promoters, we achieve efficient infection, stable integration and sustained epidermal expression of short-hairpin RNAs (shRNAs) at the requisite early developmental stage that permits analysis of their consequences to ACD.避免组织特异性启动子,就可以实现高效的感染,稳定整合和持续的表皮表达的短发夹RNA(shRNA片段)在必需的早期发育阶段,允许到ACD分析其后果
23、。 Other Sections 第 o Summary 总结 o Introduction 介绍 o Results 结果 o Discussion 讨论 o Methods Summary 方法总结 o Methods 方法 o Supplementary Material 补充材料 o References 参考文献 Results结果 ACD components control spindle orientation ACD元件控制主轴定向 LGN regulates spindle orientation and promotes planar cell divisions in
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