Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling
Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling
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DOI：
10.1371/journal.pgen.1008368
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发表时间：
2019-09-01
期刊：
影响因子：
4.5
通讯作者：
Liu, Lin
中科院分区：
文献类型：
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作者：
Liu, Na;Yin, Yu;Liu, Lin
端粒酶组分（例如，Dyskerin，TERT，TERC）突变的患者通常伴有异常表皮的症状，如色素沉着过度，皮肤过早退化，毛囊脱落，皮肤萎缩和皮肤干燥。端粒相关蛋白或端粒酶基因突变的小鼠也表现出类似的表型，与端粒缩短有关。然而，潜在的分子信号传导和机制仍然难以捉摸。在这里，我们表明，表皮的分化被破坏，导致短端粒。随着端粒长度的延长，表皮分化异常可以被挽救。此外，我们还发现Fst-BMP-Smad通路参与端粒长度对表皮分化的调控，端粒缩短与衰老和年龄相关疾病有关。此外，端粒酶基因突变导致的端粒功能障碍可导致过早衰老，如明显的皮肤萎缩和脱发。然而，将端粒功能障碍与皮肤萎缩联系起来的分子信号仍然难以捉摸。在这里，我们表明，功能失调的端粒破坏BMP/pSmad/P63信号，损害表皮干细胞的规范和分化的皮肤和毛囊。我们发现，端粒缩短介导的Terc损失上调卵泡抑素（Fst），抑制pSmad信号转导和下调P63和表皮角蛋白在ESC分化模型以及在成年发育的端粒缩短的小鼠。从机制上讲，短端粒破坏PRC 2/H3 K27 me 3介导的Fst抑制。我们的研究结果表明，由于端粒功能障碍引起的皮肤萎缩是由先前未被认识到的与Fst和BMP信号传导的联系引起的，这可以在治疗方法的开发中进行探索。
Author summary Patients with mutations in the telomerase component (eg, Dyskerin, TERT, TERC) are frequently accompanied by symptoms of abnormal epidermis, such as hyperpigmentation, premature skin degradation, hair follicle shedding, skin atrophy, and dry skin. Mice with mutations in telomere-associated proteins or telomerase genes also show similar phenotypes, associated with telomere shortening. However, the underlying molecular signaling and mechanisms remain elusive. Here, we show that the differentiation of epidermis is disrupted resulting from short telomeres. Epidermal differentiation abnormalities can be rescued as the telomere length is extended. Furthermore, we uncover that Fst-BMP-Smad pathway is implicated in regulation of epidermal differentiation by telomeres length.Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.