Asymmetric midbody inheritance during germline stem cell division in Drosophila

描述（由申请人提供）：不对称干细胞分裂通过产生一个干细胞和一个分化细胞来促进组织稳态。不对称干细胞分裂可以通过内在命运决定因素的不对称分离和/或子细胞不对称放置到不同的微环境中（即，干细胞生态位内部与外部，这指定了干细胞的身份）来实现。然而，控制不对称命运决定的分子和细胞机制却知之甚少。人们早就知道，即使在表面上对称分裂的细胞中也存在不对称。例如，在细胞质分裂的最后一步即分离过程中，质膜分裂成两个独立的膜通常只发生在连接两个姊妹细胞的中间结构的一侧。这导致另一侧的细胞遗传了中间环（MR）。这种不对称性与中心体年龄有关；含有母中心体的子细胞继承了MR残体，这表明复杂的调控机制控制了这一过程。然而，尽管有这些有趣的观察结果，这些不对称是否有任何生物学相关性尚不清楚。我们建议利用果蝇种系干细胞（GSCs）来研究GSC细胞分裂过程中不对称MR遗传的机制和相关性，这为研究多细胞组织结构和发育背景下的细胞不对称提供了一个独特的机会。我们的初步研究表明，男性和女性GSCs的MR遗传是典型的不对称的，这显然涉及中心体年龄和自噬调节的不对称。我们将通过检查MR遗传缺陷的后果来研究这种现象的潜在分子机制和生物学相关性。摘要：我们的目的是了解干细胞分裂过程中不对称细胞分裂的相关性。从拟议的研究中获得的结果可能提供一种方法来操纵干细胞的行为，用于治疗或抑制癌症的生长。

DESCRIPTION (provided by applicant): Asymmetric stem cell division contributes to tissue homeostasis by generating one stem cell and one differentiating cell. Asymmetric stem cell division can be achieved by asymmetric segregation of intrinsic fate determinants and/or asymmetric placement of daughter cells into different microenvironments (i.e., inside vs. outside of the stem cell niche, which specifies stem cell identity). Yet, the molecular and cellular mechanisms that govern asymmetric fate decision are poorly understood. It has long been known that asymmetries exist even in apparently symmetrically dividing cells. For example, during the final step of cytokinesis known as abscission, the resolution of the plasma membrane into two separate membranes normally occurs from only one side of the midbody, the structure that connects the two sister cells. This results in inheritance of the midbody ring (MR) by the cell on the other side. This asymmetry has been correlated with centrosome age; the daughter cell containing the mother centrosome inherits the MR remnant, suggesting that elaborate regulatory mechanisms control this process. However, in spite of these intriguing observations, it is not known whether these asymmetries have any biological relevance. We propose to investigate the mechanism and relevance of asymmetric MR inheritance during GSC cytokinesis, using Drosophila germline stem cells (GSCs), which offer a unique opportunity to investigate cellular asymmetries in the context of multicellular tissue architecture and development. Our preliminary study suggests that the MR inheritance during male and female GSCs is stereotypically asymmetric, which apparently involves asymmetry in centrosomal age and regulation of autophagy. We will investigate the underlying molecular mechanism and the biological relevance of this phenomenon, by examining the consequence(s) of defective MR inheritance. Lay summary: We aim to understand the relevance of asymmetric cytokinesis during stem cell division. Results obtained from the proposed research may provide a means to manipulate stem cell behavior for therapeutic usage or inhibition of cancer growth. PUBLIC HEALTH RELEVANCE: We aim to understand the relevance of asymmetric cytokinesis during stem cell division. Results obtained from the proposed research may provide a means to manipulate stem cell behavior for therapeutic usage or inhibition of cancer growth.