Disruption of Supv3L1 damages the skin and causes sarcopenia, loss of fat, and death
Disruption of Supv3L1 damages the skin and causes sarcopenia, loss of fat, and death
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DOI：
10.1007/s00335-008-9168-z
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发表时间：
2009-02-01
期刊：
影响因子：
2.5
通讯作者：
Klysik, Jan E.
中科院分区：
文献类型：
--
作者：
Paul, Erin;Cronan, Rachel;Klysik, Jan E.
Supv 3L 1是在许多物种的许多组织和细胞类型中发现的保守且普遍表达的解旋酶。在人类细胞中，SUPV 3L 1被证明可以抑制细胞凋亡和姐妹染色单体交换，并损害线粒体RNA代谢和蛋白质合成。体外实验显示SUPV 3L 1与BLM和WRN蛋白结合，表明在基因组维持过程中发挥作用。据报道，小鼠Supv 3L 1基因的破坏在早期发育阶段是胚胎致死的。我们产生了一种条件性小鼠，其中与外显子14的去除相关的表型可以在各种组织中进行测试。由Mx 1启动子驱动的Cre介导的破坏显示出生后生长延迟、寿命缩短、脂肪组织和肌肉质量损失以及严重的皮肤异常，表现为鱼鳞病、表皮增厚以及真皮和皮下组织萎缩。使用他莫昔芬激活的Esr 1/Cre驱动程序，Supv 3L 1破坏导致生长迟缓和衰老表型，包括脂肪组织和肌肉质量的损失，脊柱后凸，恶病质和过早死亡。在Mx 1-Cre小鼠中观察到的许多异常，例如以足部和尾部严重剥落为特征的角化过度，也可以在他莫昔芬诱导的Cre小鼠中检测到。角质形成细胞中Supv 3L 1的条件性消融证实了皮肤的萎缩性变化和鱼鳞病样变化。总之，这些数据表明Supv 3L 1对于维持皮肤屏障是重要的。此外，Supv 3L 1功能的丧失导致加速衰老样表型。
Supv3L1 is a conserved and ubiquitously expressed helicase found in numerous tissues and cell types of many species. In human cells, SUPV3L1 was shown to suppress apoptotic death and sister chromatid exchange, and impair mitochondrial RNA metabolism and protein synthesis. In vitro experiments revealed binding of SUPV3L1 to BLM and WRN proteins, suggesting a role in genome maintenance processes. Disruption of the Supv3L1 gene in the mouse has been reported to be embryonic lethal at early developmental stages. We generated a conditional mouse in which the phenotypes associated with the removal of exon 14 can be tested in a variety of tissues. Disruption mediated by a Mx1 promoter-driven Cre displayed a postnatal growth delay, reduced lifespan, loss of adipose tissue and muscle mass, and severe skin abnormalities manifesting as ichthyosis, thickening of the epidermis, and atrophy of the dermis and subcutaneous tissue. Using a tamoxifen-activatable Esr1/Cre driver, Supv3L1 disruption resulted in growth retardation and aging phenotypes, including loss of adipose tissue and muscle mass, kyphosis, cachexia, and premature death. Many of the abnormalities seen in the Mx1-Cre mice, such as hyperkeratosis characterized by profound scaling of feet and tail, could also be detected in tamoxifen-inducible Cre mice. Conditional ablation of Supv3L1 in keratinocytes confirmed atrophic changes in the skin and ichthyosis-like changes. Together, these data indicate that Supv3L1 is important for the maintenance of the skin barrier. In addition, loss of Supv3L1 function leads to accelerated aging-like phenotypes.