Distinct and cooperative roles of mammalian Vg1 homologs GDF1 and GDF3 during early embryonic development
Distinct and cooperative roles of mammalian Vg1 homologs GDF1 and GDF3 during early embryonic development
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DOI：
10.1016/j.ydbio.2007.08.060
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发表时间：
2007-11-15
影响因子：
2.7
通讯作者：
Ibanez, Carlos F.
中科院分区：
文献类型：
--
作者：
Andersson, Olov;Bertolino, Philippe;Ibanez, Carlos F.
Vgl是TGF-β配体超家族的一员，参与了非洲爪蟾和鸡胚中中胚层的诱导、原条的形成和左纹的形成。在小鼠中，GDF 1和GDF 3--与Vgl共享高序列同一性的两种TGF-β超家族配体--已显示独立地模拟Vgl功能的不同方面。然而，GDFI和GDF 3控制的发育过程和潜在的信号传导机制在进化上保守的程度仍不清楚。在这里，我们表明，系统发育和基因组分析表明，Gdf]是真正的哺乳动物中的Vg 1直系同源物。此外，与GDFI类似，我们发现GDF 3信号传导可以由I型受体ALK 4、II型受体ActRIIA和ActRIIB以及共受体Cripto介导，以激活Smad依赖性报告基因。当在异源细胞中表达时，GDF 1或GDF 3的天然形式不能诱导下游信号传导。这可以通过使用携带异源前结构域的嵌合构建体或通过与弗林蛋白酶前体蛋白转化酶共表达来避免，这表明天然GDFI和GDF 3前体的加工较差。出乎意料的是，与Nodal-另一种参与中胚层形成的TGF-β超家族配体-的共表达也可以暴露天然GDFI和GDF 3的活性，这表明这些配体之间的潜在新合作模式。GDFI和GDF 3在胚胎发育过程中的功能互补性通过分析其相应基因之间的遗传相互作用来研究。该分析表明，Gdf 1（-/-）; Gdf 3（-/-）复合突变体比Gdf 1_（-）或Gdf 3（-/-）单一突变体受到更严重的影响，在前内脏内胚层和中胚层的形成中存在缺陷，其重现了VgI的功能丧失，表明GDFI和GDF 3一起代表了VgI的功能性哺乳动物同源物。(c)2007年爱思唯尔公司All rights reserved.
Vgl, a member of the TGF-beta superfamily of ligands, has been implicated in the induction of mesoderm, formation of primitive streak, and leftright patterning in Xenopus and chick embryos. In mice, GDF1 and GDF3 - two TGF-beta superfamily ligands that share high sequence identity with Vgl - have been shown to independently mimic distinct aspects of Vgl's functions. However, the extent to which the developmental processes controlled by GDFI and GDF3 and the underlying signaling mechanisms are evolutionarily conserved remains unclear. Here we show that phylogenetic and genomic analyses indicate that Gdf] is the true Vg1 ortholog in mammals. In addition, and similar to GDFI, we find that GDF3 signaling can be mediated by the type I receptor ALK4, type 11 receptors ActRIIA and ActRIIB, and the co-receptor Cripto to activate Smaddependent reporter genes. When expressed in heterologous cells, the native forms of either GDF I or GDF3 were incapable of inducing downstream signaling. This could be circumvented by using chimeric constructs carrying heterologous prodomains, or by co-expression with the Furin proprotein convertase, indicating poor processing of the native GDFI and GDF3 precursors. Unexpectedly, co-expression withNodal - another TGF-beta superfamily ligand involved in mesoderm formation - could also expose the activities of native GDFI and GDF3, suggesting a potentially novel mode of cooperation between these ligands. Functional complementarity between GDFI and GDF3 during embryonic development was investigated by analyzing genetic interactions between their corresponding genes. This analysis showed that Gdf1(-/-);Gdf3(-/-) compound mutants are more severely affected than either Gdfl_ (_) or Gdf3(-/-) single mutants, with defects in the formation of anterior visceral endoderm and mesoderm that recapitulate VgI loss of function, suggesting that GDFI and GDF3 together represent the functional mammalian homologs of Vgl. (c) 2007 Elsevier Inc. All rights reserved.