Genetic basis for an evolutionary shift from ancestral preaxial to postaxial limb polarity in non-urodele vertebrates.
Genetic basis for an evolutionary shift from ancestral preaxial to postaxial limb polarity in non-urodele vertebrates.
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DOI：
10.1016/j.cub.2021.09.010
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发表时间：
2021-11-22
期刊：
影响因子：
--
通讯作者：
Mackem S
中科院分区：
文献类型：
--
作者：
Trofka A;Huang BL;Zhu J;Heinz WF;Magidson V;Shibata Y;Shi YB;Tarchini B;Stadler HS;Kabangu M;Al Haj Baddar NW;Voss SR;Mackem S
在大多数四足脊椎动物中，肢体骨骼祖细胞以轴后优势进行凝聚。后部元件（如尺骨和腓骨）先于其前部对应元件（桡骨和胫骨）出现，随后指（趾）按顺序出现，且轴后极性持续存在。唯一的例外是有尾两栖动物（蝾螈），其肢体元件以轴前极性发育，并且成年蝾螈还以具备独特的完整肢体再生能力而闻名。这种轴前优势的机制基础一直是个谜，甚至有人提出这与参与再生的新基因的获得有关。然而，最近的化石证据表明，轴前极性代表的是一种祖先状态，而非衍生状态。在此，我们报告称，小鼠中5’Hoxd（Hoxd11 - d13）基因缺失属于返祖现象，揭示了哺乳动物肢体形成过程中潜在的轴前极性。我们证明，小鼠中从轴后到轴前优势的这种转变，是由于5’Hoxd与Gli3的拮抗作用丧失，导致Gli3阻遏蛋白（Gli3R）活性过剩所致，并且这与促进前肢芽细胞过早退出细胞周期的细胞周期变化有关。我们进一步表明，在美西螈中敲低Gli3会导致肢体骨骼形成转变为轴后优势，同时出现桨状肢体芽形态扩大以及随之而来的多指（趾）现象。Gli3R活性水平的进化变化在鳍向肢体的转变中也发挥了关键作用，这似乎是四足动物肢体骨骼形成过程中从轴前极性向轴后极性转变的根本原因。
蝾螈是四足动物中独特的存在，其初级肢体轴以祖先的轴前优势形成，但其潜在基础尚不清楚。在此，特罗夫卡等人表明Gli3起着核心作用；Gli3阻遏蛋白活性升高的小鼠会恢复为轴前优势。相反，敲低Gli3会使美西螈的肢体轴从轴前极性转变为轴后极性。
In most tetrapod vertebrates, limb skeletal progenitors condense with postaxial dominance. Posterior elements (such as ulna and fibula) appear prior to their anterior counterparts (radius and tibia), followed by digit appearance order with continuing postaxial polarity. The only exceptions are urodele amphibians (salamanders), whose limb elements develop with preaxial polarity and who are also notable for their unique ability to regenerate complete limbs as adults. The mechanistic basis for this preaxial dominance has remained an enigma and has even been proposed to relate to the acquisition of novel genes involved in regeneration. However, recent fossil evidence suggests that preaxial polarity represents an ancestral rather than derived state. Here we report that 5’Hoxd (Hoxd11-d13) gene deletion in mouse is atavistic and uncovers an underlying preaxial polarity in mammalian limb formation. We demonstrate this shift from postaxial to preaxial dominance in mouse results from excess Gli3 repressor (Gli3R) activity due to the loss of 5’Hoxd-Gli3 antagonism and is associated with cell cycle changes promoting precocious cell cycle exit in the anterior limb bud. We further show that Gli3 knock-down in axolotl results in a shift to postaxial dominant limb skeleton formation, as well as expanded paddle-shaped limb bud morphology and ensuing polydactyly. Evolutionary changes in Gli3R activity level, which also played a key role in the fin-to-limb transition, appear to be fundamental to the shift from preaxial to postaxial polarity in formation of the tetrapod limb skeleton. Uniquely in salamanders, the tetrapod primary limb axis forms with ancestral preaxial dominance but the underlying basis is unknown. Here, Trofka et al. show Gli3 has a central role; mice with elevated Gli3 repressor activity revert to preaxial dominance. Conversely, Gli3 knockdown shifts the axolotl limb axis from preaxial to postaxial polarity.
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影响因子：
11.8
作者：
Lopez-Rios, Javier;Speziale, Dario;Robay, Dimitri;Scotti, Martina;Osterwalder, Marco;Nusspaumer, Gretel;Galli, Antonella;Hollaender, Georg A.;Kmita, Marie;Zeller, Rolf
通讯作者：
Zeller, Rolf
DOI：
10.1073/pnas.1919470117
发表时间：
2020-01-14
影响因子：
11.1
作者：
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通讯作者：
Ros, Marian A.
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作者：
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CAPECCHI, MR
影响因子：
8.8
作者：
Lettice LA;Devenney P;De Angelis C;Hill RE
通讯作者：
Hill RE
影响因子：
25
作者：
Madisen L;Zwingman TA;Sunkin SM;Oh SW;Zariwala HA;Gu H;Ng LL;Palmiter RD;Hawrylycz MJ;Jones AR;Lein ES;Zeng H
通讯作者：
Zeng H