Regulation of nodal and BMP signaling by tomoregulin-1 (X7365) through novel mechanisms
Regulation of nodal and BMP signaling by tomoregulin-1 (X7365) through novel mechanisms
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DOI：
10.1016/s0012-1606(02)00075-1
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发表时间：
2003-03-01
影响因子：
2.7
通讯作者：
Brivanlou, AH
中科院分区：
文献类型：
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作者：
Chang, CB;Eggen, BJL;Brivanlou, AH
在早期脊椎动物发育期间，转化生长因子β（TGFbeta）家族成员在多种过程中发挥重要作用，包括种系特化、图案形成、细胞分化、迁移和器官发生。需要严格控制TGF β的活动，以确保其在适当的时间和地点发挥作用。尽管鉴定了骨形态发生蛋白（BMP）亚家族配体的多种调节剂，但TGF β配体的激活素/nodal类的调节剂是有限的，包括卵泡抑素、Cerberus和Lefty。最近，分离出一种膜蛋白tomoregulin-1（TMEFF 1，最初命名为X7365），发现除了表皮生长因子（EGF）结构域外，还含有两个卵泡抑素模块，这表明TMEFF 1可能参与TGF β功能的调节。在这里，我们表明，不像卵泡抑素和卵泡抑素相关基因（FLRG），TMEFF 1抑制节点，但不激活素在非洲爪蟾。有趣的是，卵泡抑素模块和EGF基序都有助于淋巴结抑制。然而，含有卵泡抑素和EGF结构域的可溶性蛋白不足以抑制淋巴结; TMEFF 1在膜上的位置对其功能至关重要。这些结果表明，TMEFF 1通过一种新的机制抑制nodal。TMEFF 1也阻断中胚层，但不阻断BMP 2对表皮的诱导。与结节抑制不同，TMEFF 1调节BMP活性需要后者的胞质尾区，而卵泡抑素模块或EGF基序的缺失不会干扰TMEFF 1的BMP抑制功能。这些结果表明，TMEFF 1可能采用不同的机制，在调节节点和BMP信号。在非洲爪蟾中，TMEFF 1从中原肠胚阶段开始表达，并在神经组织衍生物中富集。这种表达模式表明，TMEFF 1可以调节节点和BMP的活动在神经图案。总之，我们的数据表明，tomoregulin-1是一种新的调节器的节点和BMP信号在早期脊椎动物胚胎发生。(C)2003 Elsevier Science（美国）。All rights reserved.
During early vertebrate development, members of the transforming growth factor beta (TGFbeta) family play important roles in a variety of processes, including germ layer specification, patterning, cell differentiation, migration, and organogenesis. The activities of TGFbetas need to be tightly controlled to ensure their function at the right time and place. Despite identification of multiple regulators of Bone Morphogenetic Protein (BMP) subfamily ligands, modulators of the activin/nodal class of TGFbeta ligands are limited, and include follistatin, Cerberus, and Lefty. Recently, a membrane protein, tomoregulin-1 (TMEFF1, originally named X7365), was isolated and found to contain two follistatin modules in addition to an Epidermal Growth Factor (EGF) domain, suggesting that TMEFF1 may participate in regulation of TGFbeta function. Here, we show that, unlike follistatin and follistatin-related gene (FLRG), TMEFF1 inhibits nodal but not activin in Xenopus. Interestingly, both the follistatin modules and the EGF motif contribute to nodal inhibition. A soluble protein containing the follistatin and the EGF domains, however, is not sufficient for nodal inhibition; the location of TMEFF1 at the membrane is essential for its function. These results suggest that TMEFF1 inhibits nodal through a novel mechanism. TMEFF1 also blocks mesodermal, but not epidermal induction by BMP2. Unlike nodal inhibition, regulation of BMP activities by TMEFF1 requires the latter's cytoplasmic tail, while deletion of either the follistatin modules or the EGF motif does not interfere with the BMP inhibitory function of TMEFF1. These results imply that TMEFF1 may employ different mechanisms in the regulation of nodal and BMP signals. In Xenopus, TMEFF1 is expressed from midgastrula stages onward and is enriched in neural tissue derivatives. This expression pattern suggests that TMEFF1 may modulate nodal and BMP activities during neural patterning. In summary, our data demonstrate that tomoregulin-1 is a novel regulator of nodal and BMP signaling during early vertebrate embryogenesis. (C) 2003 Elsevier Science (USA). All rights reserved.