The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13
The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13
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DOI：
10.1073/pnas.1919470117
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发表时间：
2020-01-14
影响因子：
11.1
通讯作者：
Ros, Marian A.
中科院分区：
文献类型：
--
作者：
Bastida, Maria Felix;Perez-Gomez, Rocio;Ros, Marian A.
在四足动物的肢体中，指头(手指或脚趾)是最容易因功能适应而发生形态变化的元素。然而，尽管它们在功能上很重要，但控制手指形态的机制仍然知之甚少。在这里，我们重点了解拇指(手指1)的特殊形态，它的获得是人类手的一项重要适应。为此，我们研究了Hoxa13突变体小鼠特定不能形成数字1的肢体。我们表明，与Hoxa13在Hoxd转录调控中的作用一致，Hoxd13在Hoxa13突变的肢体中的表达没有延伸到假定的数字1区域，因此缺乏远端Hoxx转录本，这一情况可以解释其发生。Hoxd13表达的丧失，仅在数字1区域，与Gli3抑制物活性的增加有关，Gli3抑制物是一种Hoxd负调控因子，由Gli3转录增加而导致，而Gli3转录增加又是由于Hox13副犬对Gli3调节序列施加的负调制释放所致。我们的结果表明，Hoxa13通过减少Gli3转录并使5‘Hoxd第二表达阶段得以扩展，从而在手板中建立前后不对称，从而分级地启动数字1的形成。我们的工作揭示了Gli3和Hox13 Paralog之间的相互拮抗，这对Hox和Gli3基因在发育和进化背景下的调控具有重要意义。
In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution.