Pitx controls amphioxus asymmetric morphogenesis by promoting left-side development and repressing right-side formation.
Pitx controls amphioxus asymmetric morphogenesis by promoting left-side development and repressing right-side formation.
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Pitx通过促进左侧发育和抑制右侧形成来控制文昌鱼不对称形态发生
DOI：
10.1186/s12915-021-01095-0
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发表时间：
2021-08-20
期刊：
影响因子：
5.4
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Xing C;Pan R;Hu G;Liu X;Wang Y;Li G
背景
左右（LR）不对称是双侧动物的基本特征。在脊椎动物中的研究表明，LR不对称的形成包括三个主要步骤：对称性破缺，不对称基因表达，LR形态建成。虽然在前两个事件中已经取得了很大的进展，但由于脊椎动物器官复杂的发育过程，不对称形态发生的机制仍然很大程度上未知。
结果
我们在这里解决了这个问题，通过研究Pitx基因的功能在基础脊索动物文昌鱼的不对称器官发生，不像在脊椎动物中，基本上发生在原位，不依赖于细胞迁移。文昌鱼Pitx无效突变导致左侧所有器官的丢失和右侧所有器官在左侧的不完全异位形成，而Pitx部分功能丧失导致仅一些LR器官丢失或异位形成的较温和的表型。在N1至N3期，Pitch的表达逐渐从背侧前区扩展到周围区域。这导致Lhx 3和/或Prop 1和Pit等基因的激活，这些基因对左侧器官至关重要，以及Hex和/或Nkx2.1和FoxE 4等基因的下调，这些基因是右侧器官在左侧异位形成所必需的。在Pitx突变体中，左侧表达的基因不被激活，而右侧基因不能降低左侧的表达。相反，在过度表达Pitx基因的胚胎中，左侧基因在右侧异位诱导，右侧基因被抑制。在左侧和右侧基因的上游序列中确定了几个Pitx结合位点，这些位点对于Pitx激活前者和抑制后者是必需的。
结论
结果表明：（1）Pitx是文昌鱼非对称形态发生的主要（但不是唯一）决定因子;（2）不同LR器官的发育对Pitx活性有不同的要求;（3）Pitx可能通过直接诱导左侧器官和抑制右侧器官来控制文昌鱼LR的形态发生。这些结果表明，LR器官发生在文昌鱼比在脊椎动物更依赖于Pitx。它们还提供了一些脊椎动物LR器官（如肺和心房）的分子发育机制的见解，因为它们在Pitx 2敲除小鼠中显示出右异构表型，就像Pitx突变文昌鱼中的右侧器官一样。我们的研究结果也解释了为什么有些器官，如腺垂体，在文昌鱼是不对称的位置，而在脊椎动物的对称位置。
Background
Left-right (LR) asymmetry is an essential feature of bilateral animals. Studies in vertebrates show that LR asymmetry formation comprises three major steps: symmetry breaking, asymmetric gene expression, and LR morphogenesis. Although much progress has been made in the first two events, mechanisms underlying asymmetric morphogenesis remain largely unknown due to the complex developmental processes deployed by vertebrate organs.
Results
We here addressed this question by studying Pitx gene function in the basal chordate amphioxus whose asymmetric organogenesis, unlike that in vertebrates, occurs essentially in situ and does not rely on cell migration. Pitx null mutation in amphioxus causes loss of all left-sided organs and incomplete ectopic formation of all right-sided organs on the left side, whereas Pitx partial loss-of-function leads to milder phenotypes with only some LR organs lost or ectopically formed. At the N1 to N3 stages, Pitx expression is gradually expanded from the dorsal anterior domain to surrounding regions. This leads to activation of genes like Lhx3 and/or Prop1 and Pit, which are essential for left-side organs, and downregulation of genes like Hex and/or Nkx2.1 and FoxE4, which are required for right-side organs to form ectopically on the left side. In Pitx mutants, the left-side expressed genes are not activated, while the right-side genes fail to decrease expression on the left side. In contrast, in embryos overexpressing Pitx genes, the left-side genes are induced ectopically on the right side, and the right-side genes are inhibited. Several Pitx binding sites are identified in the upstream sequences of the left-side and right-side genes which are essential for activation of the former and repression of the latter by Pitx.
Conclusions
Our results demonstrate that (1) Pitx is a major (although not the only) determinant of asymmetric morphogenesis in amphioxus, (2) the development of different LR organs have distinct requirements for Pitx activity, and (3) Pitx controls amphioxus LR morphogenesis probably through inducing left-side organs and inhibiting right-side organs directly. These findings show much more dependence of LR organogenesis on Pitx in amphioxus than in vertebrates. They also provide insight into the molecular developmental mechanism of some vertebrate LR organs like the lungs and atria, since they show a right-isomerism phenotype in Pitx2 knockout mice like right-sided organs in Pitx mutant amphioxus. Our results also explain why some organs like the adenohypophysis are asymmetrically located in amphioxus but symmetrically positioned in vertebrates.
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