Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance. However, the precise function of ATF4 in the bone marrow (BM) niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we used 4 cell-type-specific mouse Cre lines to achieve conditional knockout of in Cdh5 endothelial cells, Prx1 BM stromal cells, Osx osteoprogenitor cells, and Mx1 hematopoietic cells and uncovered the role of in niche cells and hematopoiesis. Intriguingly, depletion of in niche cells did not affect hematopoiesis; however, -deficient hematopoietic cells exhibited erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediated direct regulation of transcription, which is, in turn, involved in 40 S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil–induced stress, depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.

中文翻译：

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ATF4-RPS19BP1 轴调节核糖体生物发生以促进红细胞生成


造血分化由内在调节因子和外在造血生态位控制。激活转录因子 4 (ATF4) 在胎儿和成人造血干细胞的功能维持中起着至关重要的作用。然而，ATF4在骨髓（BM）生态位中的精确功能以及ATF4调节成人造血的机制仍然很大程度上未知。在这里，我们使用 4 个细胞类型特异性的小鼠 Cre 系来条件性敲除 Cdh5 内皮细胞、Prx1 BM 基质细胞、Osx 骨祖细胞和 Mx1 造血细胞，并揭示了其在微环境细胞和造血中的作用。有趣的是，微环境细胞的耗竭并不影响造血作用；然而，缺乏的造血细胞表现出红系分化缺陷，导致发育不良性贫血。从机制上讲，ATF4 介导转录的直接调节，进而参与 40S 核糖体亚基组装，以协调核糖体生物合成并促进红细胞生成。最后，我们证明，在 5-氟尿嘧啶诱导的应激条件下，耗竭会阻碍造血谱系的恢复，而这需要有效的核糖体生物合成。综上所述，我们的研究结果强调了 ATF4-RPS19BP1 轴在红细胞生成调节中不可或缺的作用。