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动态有丝分裂纺锤体重定位控制肠道细胞命运，影响上皮细胞稳态和寿命。

Control of Intestinal Cell Fate by Dynamic Mitotic Spindle Repositioning Influences Epithelial Homeostasis and Longevity.

机构信息

Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA; The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.

出版信息

Cell Rep. 2019 Sep 10;28(11):2807-2823.e5. doi: 10.1016/j.celrep.2019.08.014.

DOI:10.1016/j.celrep.2019.08.014
PMID:31509744
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7046008/
Abstract

Tissue homeostasis depends on precise yet plastic regulation of stem cell daughter fates. During growth, Drosophila intestinal stem cells (ISCs) adjust fates by switching from asymmetric to symmetric lineages to scale the size of the ISC population. Using a combination of long-term live imaging, lineage tracing, and genetic perturbations, we demonstrate that this switch is executed through the control of mitotic spindle orientation by Jun-N-terminal kinase (JNK) signaling. JNK interacts with the WD40-repeat protein Wdr62 at the spindle and transcriptionally represses the kinesin Kif1a to promote planar spindle orientation. In stress conditions, this function becomes deleterious, resulting in overabundance of symmetric fates and contributing to the loss of tissue homeostasis in the aging animal. Restoring normal ISC spindle orientation by perturbing the JNK/Wdr62/Kif1a axis is sufficient to improve intestinal physiology and extend lifespan. Our findings reveal a critical role for the dynamic control of SC spindle orientation in epithelial maintenance.

摘要

组织稳态依赖于对干细胞子细胞命运的精确而灵活的调节。在生长过程中，果蝇肠道干细胞 (ISCs) 通过从不对称分裂到对称分裂来调整命运，从而调节 ISC 群体的大小。我们使用长期活细胞成像、谱系追踪和遗传干扰的组合，证明这种转变是通过 Jun-N 端激酶 (JNK) 信号对有丝分裂纺锤体方向的控制来执行的。JNK 在纺锤体上与 WD40 重复蛋白 Wdr62 相互作用，并转录抑制驱动蛋白 Kif1a 以促进平面纺锤体取向。在应激条件下，该功能变得有害，导致对称命运过多，并导致衰老动物组织稳态丧失。通过干扰 JNK/Wdr62/Kif1a 轴来恢复正常的 ISC 纺锤体取向足以改善肠道生理学并延长寿命。我们的研究结果揭示了动态控制 SC 纺锤体取向在上皮细胞维持中的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/aeca6440ce19/nihms-1539607-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/288bd837e3b6/nihms-1539607-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/72b638796dac/nihms-1539607-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/4c132392a901/nihms-1539607-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/aeca6440ce19/nihms-1539607-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/288bd837e3b6/nihms-1539607-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/60d5174ce8e9/nihms-1539607-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/ea4704d21ca7/nihms-1539607-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/72b638796dac/nihms-1539607-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/4c132392a901/nihms-1539607-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/409a23b4b0c6/nihms-1539607-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b094/7046008/aeca6440ce19/nihms-1539607-f0008.jpg

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