Feedback regulation of steady-state epithelial turnover and organ size.
Feedback regulation of steady-state epithelial turnover and organ size.
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DOI：
10.1038/nature23678
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发表时间：
2017-08-31
期刊：
影响因子：
64.8
通讯作者：
O'Brien LE
中科院分区：
文献类型：
--
作者：
Liang J;Balachandra S;Ngo S;O'Brien LE
上皮器官在整个成年生命中经历稳定的更替，旧细胞不断地被干细胞分裂的后代取代。为了避免增殖或萎缩，器官的周转需要严格平衡细胞的产生和损失。然而，这种均衡的机制基础尚不清楚。利用成年果蝇的肠道，我们发现强大的精确周转是通过一种耦合机制产生的，在这种耦合机制中，肠细胞凋亡打破了干细胞分裂的反馈抑制。健康的肠细胞通过E-钙粘素抑制干细胞分裂，E-钙粘附素通过抑制EGF成熟因子菱形转录而阻止有丝分裂的EGF的分泌。单个凋亡的肠细胞通过E-钙粘素的丢失促进分裂，E-钙粘附素释放与钙粘附素相关的β-连环蛋白/Armadillo和p120-连环蛋白来诱导菱形。在死亡的肠细胞中诱导出菱形，会在离散半径内的干细胞中触发EGFR的激活。当我们阻止细胞凋亡时，E-钙粘素控制的反馈抑制了分裂，器官保留了相同数量的细胞。当我们扰乱反馈时，细胞凋亡和分裂是分离的，器官要么增殖，要么萎缩。总之，我们的工作表明，强大的细胞平衡取决于分裂与凋亡的专有偶联，这将干细胞的增殖潜力限制在需要替代细胞的准确时间和地点。通过这种方式，局部的细胞-细胞通讯产生了组织水平的动态平衡和恒定的器官大小。
Epithelial organs undergo steady-state turnover throughout adult life, with old cells being continually replaced by the progeny of stem cell divisions. To avoid hyperplasia or atrophy, organ turnover demands strict equilibration of cell production and loss. However, the mechanistic basis of this equilibrium is unknown. Using the adult Drosophila intestine, we find that robustly precise turnover arises through a coupling mechanism in which enterocyte apoptosis breaks feedback inhibition of stem cell divisions. Healthy enterocytes inhibit stem cell division through E-cadherin, which prevents secretion of mitogenic EGFs by repressing transcription of the EGF maturation factor rhomboid. Individual apoptotic enterocytes promote divisions by loss of E-cadherin, which releases cadherin-associated β-catenin/Armadillo and p120-catenin to induce rhomboid. Induction of rhomboid in the dying enterocyte triggers EGFR activation in stem cells within a discrete radius. When we block apoptosis, E-cadherin-controlled feedback suppresses divisions, and the organ retains the same number of cells. When we disrupt feedback, apoptosis and divisions are uncoupled, and the organ develops either hyperplasia or atrophy. Altogether, our work demonstrates that robust cellular balance hinges on the obligate coupling of divisions to apoptosis, which limits the proliferative potential of a stem cell to the precise time and place that a replacement cell is needed. In this manner, localized cell-cell communication gives rise to tissue-level homeostatic equilibrium and constant organ size.
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影响因子：
23.9
作者：
Jiang H;Grenley MO;Bravo MJ;Blumhagen RZ;Edgar BA
通讯作者：
Edgar BA
DOI：
10.1083/jcb.129.2.489
发表时间：
1995-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hermiston ML;Gordon JI
通讯作者：
Gordon JI
DOI：
10.1038/nrm.2015.3
发表时间：
2016-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
McCrea PD;Gottardi CJ
通讯作者：
Gottardi CJ
影响因子：
8.8
作者：
Buchon, Nicolas;Osman, Dani;Lemaitre, Bruno
通讯作者：
Lemaitre, Bruno
影响因子：
16.2
作者：
Lee, T;Luo, LQ
通讯作者：
Luo, LQ