Vertebrates show conserved left-right (L-R) asymmetry of internal organs controlled by Nodal-Pitx2/Lefty signaling [1-3]. Modifications in L-R asymmetry occur in mutants [4] and rarely in humans [5], but little is known about natural L-R changes during evolution. Here we describe changes in L-R asymmetry in Astyanax mexicanus, a teleost with ancestral surface (surface fish) and derived cave (cavefish) morphs [6]. In teleosts, Nodal-Pitx2 signaling is activated in the left lateral plate mesoderm (LPM), the cardiac tube jogs to the left and loops to the right (D-looping), and the liver and pancreas form on opposite sides of the midline. Surface fish show conventional L-R patterning, but cavefish can show Nodal-Pitx2 expression in the right LPM or bilaterally, left (L)-looping hearts, and reversed liver and pancreas asymmetry, and these reversals have no effect on survival. The Lefty1 Nodal antagonist is expressed along the surface fish and cavefish midlines, but expression of the Lefty2 antagonist is absent in the LPM of most cavefish embryos, suggesting a role for lefty2 (lft2) in changing organ asymmetry. Although CRISPR-Cas9 lft2 editing affected D-looping in surface fish, the cavefish lft2 gene showed no coding mutations, and was expressed normally during cavefish gastrulation, suggesting downregulation by regulatory changes. Reciprocal hybridization, the fertilization of cavefish eggs with surface fish sperm and vice versa, indicated that the change in cavefish L-R asymmetry is a maternal genetic effect. Our studies reveal natural changes in internal organ asymmetry during evolution and introduce A. mexicanus as a new model to study the underlying mechanisms.

中文翻译：

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鸭Cave鱼的左右内脏不对称的进化变化

脊椎动物显示受Nodal-Pitx2 / Lefty信号控制的内脏保守的左右（LR）不对称[1-3]。LR不对称性的改变发生在突变体中[4]，很少发生在人类中[5]，但是人们对进化过程中自然LR变化的了解却很少。在这里，我们描述了墨西哥Astyanax，具有祖先表面（表面鱼）和派生洞穴（洞穴鱼）形态的硬骨鱼的LR不对称性的变化[6]。在硬骨鱼中，在左侧外侧板中胚层（LPM）中激活了Nodal-Pitx2信号传导，心管向左移动并向右循环（D循环），肝脏和胰腺在中线的相对侧形成。表层鱼表现出常规的LR模式，但洞穴鱼在右LPM或双侧，左（L）环心脏以及肝脏和胰腺的不对称性反转中可显示Nodal-Pitx2表达，这些逆转对生存没有影响。Lefty1 Nodal拮抗剂沿表面鱼类和洞穴鱼的中线表达，但大多数洞穴鱼胚胎的LPM中不存在Lefty2拮抗剂的表达，这表明lefty2（lft2）在改变器官不对称性中起作用。尽管CRISPR-Cas9 lft2的编辑影响了表层鱼类的D环，但洞穴鱼lft2基因未显示编码突变，并且在洞穴鱼胃气化过程中正常表达，表明通过调节变化而下调。相互杂交，即用表面鱼类的精子使海豚卵受精，反之亦然，这表明海豚LR不对称性的改变是母体遗传效应。我们的研究揭示了进化过程中内部器官不对称性的自然变化，并介绍了墨西哥曲霉作为研究其潜在机制的新模型。