Regulation of Erythropoiesis by BMP4 and Smad5

成人骨髓中的红细胞生成主要是稳态的，在整个成人生活中产生恒定水平的红细胞。 这种情况是显着不同的胚胎发育过程中的胎儿肝脏和成人脾脏急性红细胞应激。 在这两种情况下，红细胞生成迅速产生大量的红细胞。考虑到胎儿肝脏和脾脏都是扩张性红细胞生成的部位，已经表明在发育期间调节胎儿肝脏中的红细胞生成和在红细胞应激期间调节脾脏中的红细胞生成的分子机制是相似的，但不同于稳态成人骨髓红细胞生成。这种联系在曲尾（f）基因座突变的小鼠中很明显。 f/f突变小鼠表现出严重的胎儿贫血，在出生后2周消退。 成年f/f小鼠表现出正常的稳态血液参数，然而，它们表现出对急性红细胞应激反应的严重延迟。 我们在f/f小鼠中发现了Smad 5基因的突变。 Smad 5是一种信号传导蛋白-转录因子，作用于BMP 4受体下游。 BMP 4在造血细胞的发育，特别是红系细胞的发育中起关键作用。 该提案概述了旨在研究BMP 4/Smad 5信号通路在发育过程中胎儿肝脏和脾脏对红细胞生成应激反应过程中的膨胀性红细胞生成特征中的作用的实验。 我们将利用f/f小鼠作为一种手段来剖析BMP 4和Smad 5在造血和红细胞生成中的作用。 首先，我们确定BMP 4和Smad 5在急性应激后脾中应激红系祖细胞的扩增和分化中的作用。 其次，我们将分析BMP 4和Smad 5在胚胎主动脉-性腺-中肾（AGM）区域造血干细胞和多能细胞发育中的作用。 第三，我们将分析BMP 4和Smad 5在胎肝红系祖细胞发育和分化中的作用。 这些分析将提供重要的基本信息，可用于开发贫血疗法和创伤性失血的治疗。

Erythropoiesis in the adult bone marrow is primarily homeostatic, producing a constant level of erythrocytes throughout adult life. This situation is dramatically different in the fetal liver during embryogenesis and in the adult spleen following acute erythroid stress. In both of these cases, erythropoiesis rapidly produces larger numbers of erythrocytes. Given that both the fetal liver and the spleen are sites of expansive erythropoiesis it has been suggested that the molecular mechanisms that regulate erythropoiesis in the fetal liver during development and the spleen during erythroid stress are similar, but distinct from steady state adult bone marrow erythropoiesis. This connection is evident in mice mutated at the flexed-tail (f) locus. f/f mutant mice exhibit a severe fetal anemia that resolves by 2 weeks after birth. Adult f/f mice exhibit normal steady state blood parameters, however, they exhibit a severe delay in the response to acute erythroid stress. We have identified a mutation in the Smad5 gene in f/f mice. Smad5 is a signaling protein-transcription factor that acts downstream of the BMP4 receptor. BMP4 plays a key role in the development of the development of hematopoietic cells and in particular the development of the erythroid lineage. This proposal outlines experiments designed to investigate the role of the BMP4/Smad5 signaling pathway in the expansive erythropoiesis characteristic of the fetal liver during development and the spleen during the response to erythropoietic stress. We will utilize the f/f mice as a means to dissect the role of BMP4 and Smad5 in hematopoesis and erythropoiesis. First, we determine the role of BMP4 and Smad5 in the expansion and differentiation of stress erythroid progenitors in the spleen following acute stress. Second we will analyze the role of BMP4 and Smad5 in the development of hematopoietic stem cells and multipotential cells in the Aorta- Gonad-Mesonephros (AGM) region of the embryo. Third, we will analyze the role of BMP4 and Smad5 in the development and differentiation of fetal liver erythroid progenitors. These analyses will provide important basic information that could be used to develop therapies for anemia and the treatment of traumatic blood loss.