Mammalian twisted gastrulation is essential for skeleto-lymphogenesis
Mammalian twisted gastrulation is essential for skeleto-lymphogenesis
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DOI：
10.1128/mcb.23.8.2969-2980.2003
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发表时间：
2003-04-01
影响因子：
5.3
通讯作者：
Kitamura, T
中科院分区：
文献类型：
--
作者：
Nosaka, T;Morita, S;Kitamura, T
背腹模式取决于形态发生素的局部浓度。扭曲原肠胚形成 (TSG) 调节中胚层诱导物骨形态发生蛋白 4 (BMP-4) 的细胞外可用性。然而，TSG在体内的功能仍不清楚。我们从小鼠主动脉-性腺-中肾区域分离出 TSG cDNA 作为分泌分子。在这里，我们发现 TSG 缺陷小鼠出生时是健康的，但超过一半的新生幼崽在出生后不久表现出严重的生长迟缓，并表现出侏儒症，伴有软骨内骨化延迟和淋巴细胞减少，随后在一个月内死亡。 TSG 缺陷的胸腺萎缩，并且胸腺细胞中 SMAD1 的磷酸化增强，表明胸腺中的 BMP-4 信号传导增强。由于 BMP-4 促进骨骼形成并抑制胸腺发育，我们的研究结果表明，TSG 在骨骼形成中既充当 BMP-4 激动剂，又在 T 细胞发育中充当 BMP-4 拮抗剂。尽管 TSG 缺陷小鼠的淋巴细胞减少症部分归因于缺乏活力和消瘦的全身影响，但我们的研究结果也可能为了解人类侏儒症合并免疫缺陷的发病机制提供线索。
Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.