Smad5 determines murine amnion fate through the control of bone morphogenetic protein expression and signalling levels
Smad5 determines murine amnion fate through the control of bone morphogenetic protein expression and signalling levels
复制标题
DOI：
10.1242/dev.02497
复制
发表时间：
2006-09-01
期刊：
影响因子：
4.6
通讯作者：
Zwijsen, An
中科院分区：
文献类型：
--
作者：
Bosman, Erika A.;Lawson, Kirstie A.;Zwijsen, An
Smad 5是骨形态发生蛋白（Bmp）信号传导的细胞内介质。它对于原始生殖细胞（PGC）发育、尿囊的发育和羊膜闭合是必不可少的，如Bmp信号传导的丧失所证明的。相比之下，异位PGC样细胞和局部异位血管发生和造血增厚Smad 5（M1/M1）羊膜的外观是羊膜缺陷，尚未与Bmp信号成分的损失。我们发现，在Smad 5突变小鼠的胚胎日（E）7.5时，已经可以检测到羊膜和尿囊的缺陷。然而，异位Oct 4阳性（Oct 4（+））和碱性磷酸酶阳性（AP（+））细胞在E8.5时突然出现在增厚的羊膜中，并且距离尿囊和后原条较远，表明原位命运的改变。这些异位Oct 4（+）、AP（+）细胞似乎是Stella阴性的，因此不能称为真正的PGC。我们证明了一个强大的上调Bmp 2和Bmp 4的表达，以及Erk和Smad活性，在Smad 5突变体羊膜。异位表达的几个BMP靶基因在不同的领域和区域化的存在下，细胞的几个BMP敏感的谱系在突变羊膜表明，不同水平的BMP信号可能决定细胞的命运。在野生型胚胎的外体腔中注射rBMP 4可以诱导羊膜增厚，模仿Smad 5突变体中的早期羊膜表型。这些结果支持一个模型，其中Smad 5的损失导致矛盾的增益BMP功能缺陷的羊膜。
Smad5 is an intracellular mediator of bone morphogenetic protein (Bmp) signalling. It is essential for primordial germ cell (PGC) development, for the development of the allantois and for amnion closure, as demonstrated by loss of Bmp signalling. By contrast, the appearance of ectopic PGC-like cells and regionalized ectopic vasculogenesis and haematopoiesis in thickened Smad5(m1/m1) amnion are amnion defects that have not been associated with loss of Bmp signalling components. We show that defects in amnion and allantois can already be detected at embryonic day (E) 7.5 in Smad5 mutant mice. However, ectopic Oct4-positive (Oct4(+)) and alkaline phosphatase-positive (AP(+)) cells appear suddenly in thickened amnion at E8.5, and at a remote distance from the allantois and posterior primitive streak, suggesting a change of fate in situ. These ectopic Oct4(+), AP(+) cells appear to be Stella negative and hence cannot be called bona fide PGCs. We demonstrate a robust upregulation of Bmp2 and Bmp4 expression, as well as of Erk and Smad activity, in the Smad5 mutant amnion. The ectopic expression of several Bmp target genes in different domains and the regionalized presence of cells of several Bmp-sensitive lineages in the mutant amnion suggest that different levels of Bmp signalling may determine cell fate. Injection of rBMP4 in the exocoelom of wild-type embryos can induce thickening of amnion, mimicking the early amnion phenotype in Smad5 mutants. These results support a model in which loss of Smad5 results paradoxically in gain of Bmp function defects in the amnion.