Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria-Sociedad para al Desarollo de Cantabria, 39011 Santander, Spain.
Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1090-1096. doi: 10.1073/pnas.1919470117. Epub 2020 Jan 2.
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 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in transcriptional regulation, the expression of in mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal transcripts, a circumstance that can explain its agenesis. The loss of expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a negative regulator, resulting from increased transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing transcription and by enabling expansion of the 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 and gene regulation in the context of development and evolution.
在四足动物肢体中，手指（或脚趾）是对功能适应性变化最具形态多样性的元素。然而，尽管它们具有重要的功能，但控制数字形态的机制仍知之甚少。在这里，我们专注于理解拇指（数字 1）的特殊形态，拇指的出现是人手的一个重要适应。为此，我们研究了专门不能形成第一指的小鼠突变体的肢体。我们表明，与 Hoxa13 在转录调控中的作用一致，在突变体肢体中的表达并没有延伸到假定的第一指区域，因此该区域缺乏远端的 转录物，这种情况可以解释其缺失。的表达丧失，仅在第一指区域，与Gli3 抑制剂活性的增加相关，Gli3 抑制剂是一种负调节剂，这是由于转录增加所致，而转录增加又是由于 Hox13 同源物对 调节序列的负调控的释放所致。我们的结果表明，Hoxa13 通过减少 转录并通过允许 的第二个表达阶段的扩展来作为一个层次来启动第一指的形成，从而在手板中建立前后不对称性。我们的工作揭示了 Gli3 和 Hoxa13 同源物之间的拮抗作用，这对发育和进化背景下的 和 基因调控具有重要意义。
