Co-option of an ancestral cloacal regulatory landscape during digit evolution

• 成果类型: Article
• 署名作者: Hintermann, Aurelie; Bolt, Christopher C.; Hawkins, M. Brent; Valentin, Guillaume; Lopez-Delisle, Lucille; Ryan, Madeline M.; Gitto, Sandra; Barrera Gomez, Paula; Mascrez, Benedicte; Mansour, Thomas A.; Nakamura, Tetsuya; Harris, Matthew P.; Shubin, Neil H.; Duboule, Denis
• 署名单位: University of Geneva; Swiss Federal Institutes of Technology Domain; Swiss School of Public Health (SSPH+); Ecole Polytechnique Federale de Lausanne; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Rutgers University System; Rutgers University New Brunswick; University of Chicago; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite PSL; Centre National de la Recherche Scientifique (CNRS); College de France; Stowers Institute for Medical Research
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09548-0
• 发表日期: 2025-12-04
• 关键词: global control region; hox-genes; functional evolution; expression patterns; deep homology; web server; zebrafish; origin; morphogenesis; transcription

摘要

The fin-to-limb transition in vertebrate evolution has been central to the study of how development underlies evolutionary change. In this context, the functional analysis of Hox gene regulation to infer evolutionary trajectories has been critical to explain the origin of new features. In tetrapods, the transcription of Hoxd genes in developing digits depends on a set of enhancers forming a large regulatory landscape1,2. The presence of a syntenic counterpart in zebrafish, which lacks digits, suggests deep homology3 or shared developmental foundations underlying distal fin and limbs. However, how this regulatory program evolved has remained unresolved. We genetically evaluated the function of the zebrafish Hoxd regulatory landscapes by comparatively assessing the effects of their full deletions. We show that, unlike in mice, deletion of these regions in fish does not disrupt hoxd gene transcription during distal fin development. By contrast, we found that this deficiency leads to the loss of expression within the cloaca, a structure related by ancestry to the mammalian urogenital sinus, and that distal hox13 genes are essential for correct cloacal formation. Because Hoxd gene regulation in the mouse urogenital sinus relies on enhancers located in this same chromatin domain that controls digit development, we propose that the current regulatory landscape active in distal limbs was co-opted as a whole in tetrapods from a pre-existing cloacal regulatory machinery.