Chen Canhe, Ware Stephanie M, Sato Akira, Houston-Hawkins Dianne E, Habas Raymond, Matzuk Martin M, Shen Michael M, Brown Chester W
Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Development. 2006 Jan;133(2):319-29. doi: 10.1242/dev.02210.
The formation of the anterior visceral endoderm (AVE) in the pre-gastrulation mouse embryo represents a crucial event in patterning of the anterior-posterior axis. Here, we show that the transforming growth factor beta (Tgfbeta) family member Gdf3 (growth-differentiation factor 3), a close relative of Xenopus Vg1, resembles the Tgfbeta ligand Nodal in both its signaling activity and its role in AVE formation in vivo. Thus, in cell culture, Gdf3 signaling requires the EGF-CFC co-receptor Cripto and can be inhibited by Lefty antagonists. In Xenopus embryos, Gdf3 misexpression results in secondary axis formation, and induces morphogenetic elongation and mesendoderm formation in animal caps. In mouse embryos, Gdf3 is expressed in the inner cell mass and epiblast, and null mutants frequently exhibit abnormal formation or positioning of the AVE. This phenotype correlates with defects in mesoderm and definitive endoderm formation, as well as abnormal Nodal expression levels. Our findings indicate that Gdf3 acts in a Nodal-like signaling pathway in pre-gastrulation development, and provide evidence for the functional conservation of Vg1 activity in mice.
原肠胚形成前的小鼠胚胎中，前内脏内胚层（AVE）的形成是前后轴模式形成过程中的一个关键事件。在此，我们表明，转化生长因子β（Tgfbeta）家族成员Gdf3（生长分化因子3），即非洲爪蟾Vg1的近亲，在其信号活性以及在体内AVE形成中的作用方面，均类似于Tgfbeta配体Nodal。因此，在细胞培养中，Gdf3信号传导需要EGF-CFC共受体Cripto，并且可被Lefty拮抗剂抑制。在非洲爪蟾胚胎中，Gdf3的错误表达会导致次级轴的形成，并在动物帽中诱导形态发生延长和中内胚层形成。在小鼠胚胎中，Gdf3在内细胞团和上胚层中表达，而基因敲除突变体经常表现出AVE形成或定位异常。这种表型与中胚层和定形内胚层形成的缺陷以及Nodal表达水平异常相关。我们的研究结果表明，Gdf3在原肠胚形成前的发育过程中以类似Nodal的信号通路发挥作用，并为Vg1活性在小鼠中的功能保守性提供了证据。
