The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo.
The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo.
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发表时间：
1999-06
期刊：
影响因子：
4.6
通讯作者：
Zhenyu Gu;Ellen M. Reynolds;Jihwan Song;Hong Lei;Alie Feijen;Lian Yu;Weiwu He;D. Maclaughlin;J. V. Raaij;Patricia K. Donahoe;En Li
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文献类型：
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作者：
Zhenyu Gu;Ellen M. Reynolds;Jihwan Song;Hong Lei;Alie Feijen;Lian Yu;Weiwu He;D. Maclaughlin;J. V. Raaij;Patricia K. Donahoe;En Li
ActRIA（或ALK 2），转化生长因子-β（TGF-β）超家族的I型受体之一，可以分别结合激活素和骨形态发生蛋白（BMP）与激活素和BMP II型受体。在小鼠中，ActRIA在原肠胚形成之前主要在胚外内脏内胚层中表达，随后在原肠胚形成期间在胚胎和胚外细胞中表达。为了阐明其在小鼠发育中的功能，我们通过基因打靶破坏ActRIA的跨膜结构域。我们发现，突变纯合子的胚胎在早期原肠胚形成阶段被逮捕，显示异常内脏内胚层形态和中胚层形成的严重破坏。为了确定ActRIA在原肠胚形成期间在哪个胚层中起作用，我们进行了相互嵌合体分析。(1)将纯合突变ES细胞注射到野生型囊胚中，能够在嵌合体胚胎中形成所有三个定形胚层。然而，嵌合体中突变ES细胞的高贡献破坏了早期体节阶段的正常发育。(2)与ActRIA在胚外细胞中的表达一致，野生型ES细胞未能挽救嵌合体中的原肠胚形成缺陷，其中胚外外胚层和内脏内胚层来源于纯合突变胚泡。此外，HNF 4的表达，一个关键的内脏内胚层特异性转录调节因子，显着减少突变体胚胎。总之，我们的研究结果表明，ActRIA在胚胎外细胞在早期原肠胚形成中起着重要作用，而ActRIA功能也需要在胚胎组织在小鼠后期的发展。
ActRIA (or ALK2), one of the type I receptors of the transforming growth factor-beta (TGF-beta) superfamily, can bind both activin and bone morphogenetic proteins (BMPs) in conjunction with the activin and BMP type II receptors, respectively. In mice, ActRIA is expressed primarily in the extraembryonic visceral endoderm before gastrulation and later in both embryonic and extraembryonic cells during gastrulation. To elucidate its function in mouse development, we disrupted the transmembrane domain of ActRIA by gene targeting. We showed that embryos homozygous for the mutation were arrested at the early gastrulation stage, displaying abnormal visceral endoderm morphology and severe disruption of mesoderm formation. To determine in which germ layer ActRIA functions during gastrulation, we performed reciprocal chimera analyses. (1) Homozygous mutant ES cells injected into wild-type blastocysts were able to contribute to all three definitive germ layers in chimeric embryos. However, a high contribution of mutant ES cells in chimeras disrupted normal development at the early somite stage. (2) Consistent with ActRIA expression in the extraembryonic cells, wild-type ES cells failed to rescue the gastrulation defect in chimeras in which the extraembryonic ectoderm and visceral endoderm were derived from homozygous mutant blastocysts. Furthermore, expression of HNF4, a key visceral endoderm-specific transcription regulatory factor, was significantly reduced in the mutant embryos. Together, our results indicate that ActRIA in extraembryonic cells plays a major role in early gastrulation, whereas ActRIA function is also required in embryonic tissues during later development in mice.