Laboratory of Vertebrate Embryology, The Rockefeller University, 1230 York Ave., New York, NY 10065, USA.
Dev Biol. 2011 Feb 1;350(1):13-23. doi: 10.1016/j.ydbio.2010.09.016. Epub 2010 Sep 27.
The specification of left-right asymmetry is an evolutionarily conserved developmental process in vertebrates. The interplay between two TGFβ ligands, Derrière/GDF1 and Xnr1/Nodal, together with inhibitors such as Lefty and Coco/Cerl2, have been shown to provide the signals that lead to the establishment of laterality. However, molecular events leading to and following these signals remain mostly unknown. We find that APOBEC2, a member of the cytidine deaminase family of DNA/RNA editing enzymes, is induced by TGFβ signaling, and that its activity is necessary to specify the left-right axis in Xenopus and zebrafish embryos. Surprisingly, we find that APOBEC2 selectively inhibits Derrière, but not Xnr1, signaling. The inhibitory effect is conserved, as APOBEC2 blocks TGFβ signaling, and promotes muscle differentiation, in a mammalian myoblastic cell line. This demonstrates for the first time that a putative RNA/DNA editing enzyme regulates TGFβ signaling and plays a major role in development.
左右不对称的特征是脊椎动物中一种进化上保守的发育过程。两种 TGFβ 配体，Derrière/GDF1 和 Xnr1/Nodal，以及抑制剂如 Lefty 和 Coco/Cerl2，相互作用，提供了导致左右对称的信号。然而，导致和跟随这些信号的分子事件在很大程度上仍然未知。我们发现 APOBEC2，一种胞嘧啶脱氨酶家族的 DNA/RNA 编辑酶的成员，被 TGFβ 信号诱导，其活性对于指定 Xenopus 和斑马鱼胚胎的左右轴是必要的。令人惊讶的是，我们发现 APOBEC2 选择性地抑制 Derrière，但不抑制 Xnr1 的信号。这种抑制作用是保守的，因为 APOBEC2 阻断 TGFβ 信号，并促进哺乳动物成肌细胞系中的肌肉分化。这首次证明了一种假定的 RNA/DNA 编辑酶调节 TGFβ 信号，并在发育中发挥主要作用。
