Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide/Junta de Andalucía, Sevilla, Spain.
Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL, USA.
Nat Genet. 2018 Apr;50(4):504-509. doi: 10.1038/s41588-018-0080-5. Epub 2018 Mar 19.
Despite their evolutionary, developmental and functional importance, the origin of vertebrate paired appendages remains uncertain. In mice, a single enhancer termed ZRS is solely responsible for Shh expression in limbs. Here, zebrafish and mouse transgenic assays trace the functional equivalence of ZRS across the gnathostome phylogeny. CRISPR/Cas9-mediated deletion of the medaka (Oryzias latipes) ZRS and enhancer assays identify the existence of ZRS shadow enhancers in both teleost and human genomes. Deletion of both ZRS and shadow ZRS abolishes shh expression and completely truncates pectoral fin formation. Strikingly, deletion of ZRS results in an almost complete ablation of the dorsal fin. This finding indicates that a ZRS-Shh regulatory module is shared by paired and median fins and that paired fins likely emerged by the co-option of developmental programs established in the median fins of stem gnathostomes. Shh function was later reinforced in pectoral fin development with the recruitment of shadow enhancers, conferring additional robustness.
尽管脊椎动物成对附肢在进化、发育和功能上具有重要意义,但它们的起源仍然不确定。在小鼠中,一个名为 ZRS 的单一增强子仅负责 Shh 在四肢中的表达。在这里,通过斑马鱼和小鼠转基因分析,追踪了 ZRS 在颌形动物进化枝中的功能等效性。CRISPR/Cas9 介导的斑点叉尾鮰(Oryzias latipes)ZRS 的缺失和增强子分析鉴定了 ZRS 影子增强子在硬骨鱼和人类基因组中的存在。ZRS 和影子 ZRS 的缺失均会导致 shh 表达的缺失,并完全截断胸鳍的形成。引人注目的是,ZRS 的缺失导致背鳍几乎完全消失。这一发现表明,一个 ZRS-Shh 调控模块被成对的和中线的鳍所共享,并且成对的鳍可能是通过在颌形动物的中线鳍中建立的发育程序的共同作用而出现的。Shh 的功能在胸鳍的发育过程中得到了影子增强子的进一步强化,赋予了额外的稳健性。
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