Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo
Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo
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DOI：
10.1242/dev.01248
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发表时间：
2004-08-01
期刊：
影响因子：
4.6
通讯作者：
Robertson, EJ
中科院分区：
文献类型：
--
作者：
Chu, GC;Dunn, NR;Robertson, EJ
遗传和生化数据已证实Smad4是转化生长因子β(TGFbeta)分泌配体超家族的关键细胞内效应因子。在小鼠中，Smad4缺失的胚胎不原肠形成，这一表型与其他TGFbeta相关信号成分的丢失一致。嵌合分析揭示了Smad4在胚胎外谱系中的主要需求；然而，在胚胎内部，对Smad4在原肠形成和谱系指定过程中的特定作用的表征仍然有限。我们已经利用Smad4条件等位基因来特异性地灭活小鼠早期上胚中的Smad4基因。Smad4在该组织中的丢失导致了对前原始条纹的衍生物，如前脊索板、结节、脊索和最终内胚层的严重模式的失败。与这些局灶性缺陷相反，许多在中胚层形成和图案化过程中涉及的具有良好特征的转化生长因子β和BMP调节过程令人惊讶地未受影响。突变胚胎形成丰富的胚外中胚层，包括尿囊膜、发育不全的心脏和中等原始条纹的衍生物，如体节和侧板中胚层。因此，外胚层中Smad4的缺失不会导致整体发育异常，而会导致局限性的图案缺陷。这些结果表明，Smad4在早期胚胎发育过程中增强了TGFbeta相关信号的一部分，但对其他信号是必不可少的。
Genetic and biochemical data have identified Smad4 as a key intracellular effector of the transforming growth factor beta (TGFbeta) superfamily of secreted ligands. In mouse, Smad4-null embryos do not gastrulate, a phenotype consistent with loss of other TGFbeta-related signaling components. Chimeric analysis reveals a primary requirement for Smad4 in the extra-embryonic lineages; however, within the embryo proper, characterization of the specific roles of Smad4 during gastrulation and lineage specification remains limited. We have employed a Smad4 conditional allele to specifically inactivate the Smad4 gene in the early mouse epiblast. Loss of Smad4 in this tissue results in a profound failure to pattern derivatives of the anterior primitive streak, such as prechordal plate, node, notochord and definitive endoderm. In contrast to these focal defects, many well-characterized TGFbeta- and Bmp- regulated processes involved in mesoderm formation and patterning are surprisingly unaffected. Mutant embryos form abundant extra-embryonic mesoderm, including allantois, a rudimentary heart and middle primitive streak derivatives such as somites and lateral plate mesoderm. Thus, loss of Smad4 in the epiblast results not in global developmental abnormalities but instead in restricted patterning defects. These results suggest that Smad4 potentiates a subset of TGFbeta-related signals during early embryonic development, but is dispensable for others.