Stevens Jonathan, Ermakov Alexander, Braganca Jose, Hilton Helen, Underhill Peter, Bhattacharya Shoumo, Brown Nigel A, Norris Dominic P
MRC Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK.
BMC Dev Biol. 2010 May 20;10:54. doi: 10.1186/1471-213X-10-54.
Vertebrates show clear asymmetry in left-right (L-R) patterning of their organs and associated vasculature. During mammalian development a cilia driven leftwards flow of liquid leads to the left-sided expression of Nodal, which in turn activates asymmetric expression of the transcription factor Pitx2. While Pitx2 asymmetry drives many aspects of asymmetric morphogenesis, it is clear from published data that additional asymmetrically expressed loci must exist.
A L-R expression screen identified the cytoskeletally-associated gene, actin binding lim protein 1 (Ablim1), as asymmetrically expressed in both the node and left lateral plate mesoderm (LPM). LPM expression closely mirrors that of Nodal. Significantly, Ablim1 LPM asymmetry was detected in the absence of detectable Nodal. In the node, Ablim1 was initially expressed symmetrically across the entire structure, resolving to give a peri-nodal ring at the headfold stage in a flow and Pkd2-dependent manner. The peri-nodal ring of Ablim1 expression became asymmetric by the mid-headfold stage, showing stronger right than left-sided expression. Node asymmetry became more apparent as development proceeded; expression retreated in an anticlockwise direction, disappearing first from the left anterior node. Indeed, at early somite stages Ablim1 shows a unique asymmetric expression pattern, in the left lateral plate and to the right side of the node.
Left LPM Ablim1 is expressed in the absence of detectable LPM Nodal, clearly revealing existence of a Pitx2 and Nodal-independent left-sided signal in mammals. At the node, a previously unrecognised action of early nodal flow and Pkd2 activity, within the pit of the node, influences gene expression in a symmetric manner. Subsequent Ablim1 expression in the peri-nodal ring reveals a very early indication of L-R asymmetry. Ablim1 expression analysis at the node acts as an indicator of nodal flow. Together these results make Ablim1 a candidate for controlling aspects of L-R identity and patterning.
脊椎动物的器官及其相关脉管系统在左右（L-R）模式上表现出明显的不对称性。在哺乳动物发育过程中，由纤毛驱动的液体向左流动导致Nodal在左侧表达，进而激活转录因子Pitx2的不对称表达。虽然Pitx2的不对称性驱动了不对称形态发生的许多方面，但从已发表的数据来看，显然还存在其他不对称表达的基因座。
一项左右表达筛选确定了与细胞骨架相关的基因——肌动蛋白结合lim蛋白1（Ablim1），它在节点和左侧侧板中胚层（LPM）中均不对称表达。LPM中的表达与Nodal的表达密切相关。值得注意的是，在未检测到Nodal的情况下，仍检测到Ablim1在LPM中的不对称性。在节点中，Ablim1最初在整个结构中对称表达，在头褶期以流动和多囊蛋白2（Pkd2）依赖的方式形成一个节点周围环。到中头褶期，Ablim1表达的节点周围环变得不对称，右侧表达强于左侧。随着发育的进行，节点不对称性变得更加明显；表达沿逆时针方向退缩，首先从左前节点消失。事实上，在早期体节阶段，Ablim1在左侧侧板和节点右侧呈现独特的不对称表达模式。
在未检测到LPM中Nodal的情况下，左侧LPM中仍表达Ablim1，这清楚地揭示了哺乳动物中存在一个独立于Pitx2和Nodal的左侧信号。在节点处，早期节点流动和Pkd2活性在节点凹陷内以前未被认识到的作用，以对称方式影响基因表达。随后Ablim1在节点周围环中的表达揭示了左右不对称的非常早期迹象。对节点处Ablim1表达的分析可作为节点流动的指标。这些结果共同使Ablim1成为控制左右身份和模式方面的一个候选基因。
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