Schneider A, Mijalski T, Schlange T, Dai W, Overbeek P, Arnold H H, Brand T
Department of Cell and Molecular Biology, Technical University of Braunschweig, Germany.
Curr Biol. 1999 Aug 26;9(16):911-4. doi: 10.1016/s0960-9822(99)80397-2.
Vertebrate internal organs display invariant left-right (L-R) asymmetry. A signalling cascade that sets up L-R asymmetry has recently been identified (reviewed in [1]). On the right side of Hensen's node, activin represses Sonic hedgehog (Shh) expression and induces expression of the genes for the activin receptor (ActRIIa) and fibroblast growth factor-8 (FGF8) [2] [3]. On the left side, Shh induces nodal expression in lateral plate mesoderm (LPM); nodal in turn upregulates left-sided expression of the bicoid-like homeobox gene Pitx2 [4] [5] [6]. Here, we found that the homeobox gene NKX3.2 is asymmetrically expressed in the anterior left LPM and in head mesoderm in the chick embryo. Misexpression of the normally left-sided signals Nodal, Lefty2 and Shh on the right side, or ectopic application of retinoic acid (RA), resulted in upregulation of NKX3.2 contralateral to its normal expression in left LPM. Ectopic application of FGF8 on the left side blocked NKX3.2 expression, whereas the FGF receptor-1 (FGFR-1) antagonist SU5402, implanted on the right side, resulted in bilateral NKX3.2 expression in the LPM, suggesting that FGF8 is an important negative determinant of asymmetric NKX3.2 expression. NKX3.2 expression was also found to be asymmetric in the mouse LPM but, unlike in the chick, it was expressed in the right LPM. In the inversion of embryonic turning (inv) mouse mutant, which has aberrant L-R development, NKX3.2 was expressed predominantly on the left side. Thus, NKX3.2 transcripts accumulate on opposite sides of mouse and chick embryos although, in both the mouse and chick, NKX3.2 expression is controlled by the L-R signalling pathways.
脊椎动物的内部器官呈现出恒定的左右不对称性。最近已经确定了一个建立左右不对称性的信号级联反应（相关综述见[1]）。在亨森结的右侧，激活素抑制音猬因子（Shh）的表达，并诱导激活素受体（ActRIIa）和成纤维细胞生长因子8（FGF8）基因的表达[2][3]。在左侧，Shh诱导侧板中胚层（LPM）中Nodal的表达；Nodal进而上调类双尾同源框基因Pitx2在左侧的表达[4][5][6]。在这里，我们发现同源框基因NKX3.2在鸡胚的前左侧LPM和头部中胚层中不对称表达。正常情况下在左侧表达的信号Nodal、Lefty2和Shh在右侧的错误表达，或视黄酸（RA）的异位应用，导致NKX3.2在与其在左侧LPM中正常表达相反的一侧上调。在左侧异位应用FGF8会阻断NKX3.2的表达，而植入右侧的FGF受体-1（FGFR-1）拮抗剂SU5402导致LPM中NKX3.2的双侧表达，这表明FGF8是不对称NKX3.2表达的重要负向决定因素。还发现NKX3.2在小鼠LPM中也不对称表达，但与鸡不同的是，它在右侧LPM中表达。在具有异常左右发育的胚胎翻转（inv）小鼠突变体中，NKX3.2主要在左侧表达。因此，尽管在小鼠和鸡中，NKX3.2的表达都受左右信号通路控制，但NKX3.2转录本在小鼠和鸡胚胎的相反两侧积累。
