A non-canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis.
A non-canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis.
复制标题
DOI：
10.1371/journal.pone.0003364
复制
发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Kishi S
中科院分区：
文献类型：
--
作者：
Imamura S;Uchiyama J;Koshimizu E;Hanai J;Raftopoulou C;Murphey RD;Bayliss PE;Imai Y;Burns CE;Masutomi K;Gagos S;Zon LI;Roberts TM;Kishi S
尽管端粒酶的表达对维持端粒的稳态至关重要，但越来越多的证据表明，TERT蛋白可以发挥独立于这一中心功能的生理作用。为了进一步研究端粒酶在脊椎动物发育中的作用，对斑马鱼端粒酶逆转录酶(ZTERT)进行了功能鉴定。在zTERT基因敲除后，斑马鱼胚胎显示出端粒酶活性降低并存活，但由于异常造血而导致全血细胞减少。TERT缺失的斑马鱼胚胎中的血细胞数量显著减少，造血细胞分化受损，而其他体细胞谱系在形态上没有受到影响。尽管zTERT基因敲除会破坏原始和最终的造血，但在早期发育过程中，端粒长度并没有明显改变。诱导的P53缺失以及抗凋亡蛋白Bcl2和E1B 19K的过度表达显著缓解了zTERT基因敲除引起的血细胞数量的减少，但对血细胞分化的损害没有影响。令人惊讶的是，只有zTERT的逆转录酶基序是至关重要的，但zTERT的端粒酶RNA结合域并不是拯救完整造血所必需的。因此，这是第一次证明了TERT的非规范催化活性，这与脊椎动物造血过程中所需的“真正的”端粒酶活性不同。另一方面，在没有端粒功能障碍的情况下，zTERT缺陷通过对关键调控因子的基因表达产生强大而特异的影响而导致造血缺陷。这些结果表明，TERT在脊椎动物的造血细胞分化和存活中发挥着非典型的作用，而与其在端粒稳态中的作用无关。这些数据还提供了对TERT在脊椎动物发育过程中调节造血干/祖细胞规格的非规范途径的洞察。(276字)
Although it is clear that telomerase expression is crucial for the maintenance of telomere homeostasis, there is increasing evidence that the TERT protein can have physiological roles that are independent of this central function. To further examine the role of telomerase during vertebrate development, the zebrafish telomerase reverse transcriptase (zTERT) was functionally characterized. Upon zTERT knockdown, zebrafish embryos show reduced telomerase activity and are viable, but develop pancytopenia resulting from aberrant hematopoiesis. The blood cell counts in TERT-depleted zebrafish embryos are markedly decreased and hematopoietic cell differentiation is impaired, whereas other somatic lineages remain morphologically unaffected. Although both primitive and definitive hematopoiesis is disrupted by zTERT knockdown, the telomere lengths are not significantly altered throughout early development. Induced p53 deficiency, as well as overexpression of the anti-apoptotic proteins Bcl-2 and E1B-19K, significantly relieves the decreased blood cells numbers caused by zTERT knockdown, but not the impaired blood cell differentiation. Surprisingly, only the reverse transcriptase motifs of zTERT are crucial, but the telomerase RNA-binding domain of zTERT is not required, for rescuing complete hematopoiesis. This is therefore the first demonstration of a non-canonical catalytic activity of TERT, which is different from “authentic” telomerase activity, is required for during vertebrate hematopoiesis. On the other hand, zTERT deficiency induced a defect in hematopoiesis through a potent and specific effect on the gene expression of key regulators in the absence of telomere dysfunction. These results suggest that TERT non-canonically functions in hematopoietic cell differentiation and survival in vertebrates, independently of its role in telomere homeostasis. The data also provide insights into a non-canonical pathway by which TERT functions to modulate specification of hematopoietic stem/progenitor cells during vertebrate development. (276 words)
登录
查看更多内容
影响因子：
30.8
作者：
Brownlie, A;Donovan, A;Zon, LI
通讯作者：
Zon, LI
影响因子：
20.3
作者：
Craven, SE;French, D;Rosenthal, A
通讯作者：
Rosenthal, A
影响因子：
5.2
作者：
Armstrong, L;Saretzki, G;Lako, M
通讯作者：
Lako, M
影响因子：
5.3
作者：
Chiang, YJ;Hemann, MT;Hodes, RJ
通讯作者：
Hodes, RJ
影响因子：
4.5
作者：
Choi J;Southworth LK;Sarin KY;Venteicher AS;Ma W;Chang W;Cheung P;Jun S;Artandi MK;Shah N;Kim SK;Artandi SE
通讯作者：
Artandi SE