Sox6 is necessary for efficient erythropoiesis in adult mice under physiological and anemia-induced stress conditions.
Sox6 is necessary for efficient erythropoiesis in adult mice under physiological and anemia-induced stress conditions.
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DOI：
10.1371/journal.pone.0012088
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发表时间：
2010-08-09
期刊：
影响因子：
3.7
通讯作者：
Lefebvre V
中科院分区：
文献类型：
--
作者：
Dumitriu B;Bhattaram P;Dy P;Huang Y;Quayum N;Jensen J;Lefebvre V
最终的红血球生成是一生中一个至关重要的过程。它在生理条件下的基础活性和在贫血诱导的应激条件下的增加活性都受到促红细胞生成素激素的高度刺激。转录因子Sox6以前被证明除了促红细胞生成素信号外，还可以共同促进胎儿红细胞生成，但它在成年期的重要性和作用机制尚不清楚。我们在这里使用了Sox6条件性零小鼠和分子检测来解决这些问题。Sox6fl/flErGFPCre成年小鼠红细胞中缺乏Sox6，在生理条件下表现为代偿性贫血、红细胞发育缺陷、红细胞不等、寿命短的红细胞，证明Sox6促进基础红细胞生成。他莫昔芬对Sox6fl/flCaggCreer小鼠的治疗以及时可控的方式诱导了广泛的Sox6失活，并导致网织红细胞生成之前的红细胞缺陷，表明在没有Sox6的情况下，红细胞生成障碍是贫血的主要原因而不是后果。25%的Sox6fl/flErGFPCre小鼠在苯肼诱发急性贫血后4~5天死亡。其他人恢复得很慢。他们迅速提高了他们的促红细胞生成素水平，并扩大了他们的红系祖细胞池，但随后表现出严重的红细胞和网织红细胞缺陷。因此，SOX6在应激性红细胞生成的成熟期是必不可少的，紧接着是促红细胞生成素依赖的放大阶段。SOX6失活导致胚胎珠蛋白基因上调，但胚胎珠蛋白链仍然稀少，显然无关紧要。Sox6失活还导致红系末端标志物的下调，包括抗凋亡因子Bcl2l1基因的下调，体外实验表明，Sox6直接上调Bcl2l1，使其位于促红细胞生成素信号的下游和之外。这项研究表明，在基础和应激条件下，Sox6对于成年小鼠的有效红细胞生成是必要的。它主要参与提高红系细胞的存活率和成熟过程，并至少部分通过上调bcl2l1起作用。
Definitive erythropoiesis is a vital process throughout life. Both its basal activity under physiological conditions and its increased activity under anemia-induced stress conditions are highly stimulated by the hormone erythropoietin. The transcription factor Sox6 was previously shown to enhance fetal erythropoiesis together and beyond erythropoietin signaling, but its importance in adulthood and mechanisms of action remain unknown. We used here Sox6 conditional null mice and molecular assays to address these questions. Sox6fl/flErGFPCre adult mice, which lacked Sox6 in erythroid cells, exhibited compensated anemia, erythroid cell developmental defects, and anisocytotic, short-lived red cells under physiological conditions, proving that Sox6 promotes basal erythropoiesis. Tamoxifen treatment of Sox6fl/flCaggCreER mice induced widespread inactivation of Sox6 in a timely controlled manner and resulted in erythroblast defects before reticulocytosis, demonstrating that impaired erythropoiesis is a primary cause rather than consequence of anemia in the absence of Sox6. Twenty five percent of Sox6fl/flErGFPCre mice died 4 or 5 days after induction of acute anemia with phenylhydrazine. The others recovered slowly. They promptly increased their erythropoietin level and amplified their erythroid progenitor pool, but then exhibited severe erythroblast and reticulocyte defects. Sox6 is thus essential in the maturation phase of stress erythropoiesis that follows the erythropoietin-dependent amplification phase. Sox6 inactivation resulted in upregulation of embryonic globin genes, but embryonic globin chains remained scarce and apparently inconsequential. Sox6 inactivation also resulted in downregulation of erythroid terminal markers, including the Bcl2l1 gene for the anti-apoptotic factor Bcl-xL, and in vitro assays indicated that Sox6 directly upregulates Bcl2l1 downstream of and beyond erythropoietin signaling. This study demonstrates that Sox6 is necessary for efficient erythropoiesis in adult mice under both basal and stress conditions. It is primarily involved in enhancing the survival rate and maturation process of erythroid cells and acts at least in part by upregulating Bcl2l1.
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