Mammalian-specific ectodermal enhancers control the expression of Hoxc genes in developing nails and hair follicles.
Mammalian-specific ectodermal enhancers control the expression of Hoxc genes in developing nails and hair follicles.
复制标题
DOI：
10.1073/pnas.2011078117
复制
发表时间：
2020-12-01
影响因子：
11.1
通讯作者：
Ros MA
中科院分区：
文献类型：
--
作者：
Fernandez-Guerrero M;Yakushiji-Kaminatsui N;Lopez-Delisle L;Zdral S;Darbellay F;Perez-Gomez R;Bolt CC;Sanchez-Martin MA;Duboule D;Ros MA
在这项研究中，我们报告了HoxC基因簇在一些外胚层器官发育中独特且必要的功能，缺乏Hoxc 13功能的小鼠表现出的头发和指甲表型以及先天性无甲症（没有指甲）都说明了这一点。完整的HoxC簇突变体。我们发现，Hoxc基因在胚胎肢外胚层中以共线方式被激活，随后在发育中的指甲和头发中转录。我们确定了两个位于HoxC簇上游的拟南芥特异性增强子，其显示出独特的外胚层特异性。单个或组合的增强子缺失表明，它们在头发和指甲发育过程中联合作用，以提高几个Hoxc基因的转录水平。脊椎动物Hox基因对主体轴发育过程中结构的建立至关重要。随后，它们在组织次级轴结构（如附属物）或在出生后阶段和成年期的体内平衡中发挥重要作用。在这里，我们以小鼠肢芽为模型，分析它们在外胚层隔室中难以捉摸的功能。我们报告说，HoxC基因簇被增选在远端肢体外胚层，在那里它被激活的时间共线性规则被转录。这些外胚层细胞随后产生各种角化器官，如指甲或爪。因此，HoxC簇的缺失导致小鼠缺乏指甲（无甲症），这是一种比先前报道的Hoxc13功能丧失更强的病症，Hoxc13是人类患者外胚层发育不良9（ECTD9）的致病基因。我们进一步确定了位于HoxC基因簇上游的两个拟南芥特异性外胚层增强子，它们共同调节头发和指甲外胚层器官中Hoxc基因的表达。这些调控元件单独或组合的缺失揭示了外胚层中Hoxc基因调控的强定量组分，表明这两个增强子可能与哺乳动物分类群一起沿着进化，以提供毛发和指甲充分发育所需的HOXC蛋白水平。
In this study, we report a unique and necessary function for the HoxC gene cluster in the development of some ectodermal organs, as illustrated both by the hair and nail phenotype displayed by mice lacking the Hoxc13 function and by the congenital anonychia (absence of nails) in full HoxC cluster mutants. We show that Hoxc genes are activated in a colinear manner in the embryonic limb ectoderm and are subsequently transcribed in developing nails and hairs. We identify two mammalian-specific enhancers located upstream of the HoxC cluster, which display an exclusive ectodermal specificity. Individual or combined enhancer deletions suggest that they act in combination to raise the transcription level of several Hoxc genes during hair and nail development. Vertebrate Hox genes are critical for the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here, we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that the HoxC gene cluster was co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws. Accordingly, deletion of the HoxC cluster led to mice lacking nails (anonychia), a condition stronger than the previously reported loss of function of Hoxc13, which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two mammalian-specific ectodermal enhancers located upstream of the HoxC gene cluster, which together regulate Hoxc gene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation of Hoxc genes in the ectoderm, suggesting that these two enhancers may have evolved along with the mammalian taxon to provide the level of HOXC proteins necessary for the full development of hair and nail.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.95.22.13042
发表时间：
1998-10-27
影响因子：
11.1
作者：
Godwin, AR;Stadler, HS;Capecchi, MR
通讯作者：
Capecchi, MR
影响因子：
3.9
作者：
Farooq, Muhammad;Kurban, Mazen;Shimomura, Yutaka
通讯作者：
Shimomura, Yutaka
影响因子：
4.6
作者：
Hashimoto M;Takemoto T
通讯作者：
Takemoto T
影响因子：
--
作者：
Holland, Peter W. H.
通讯作者：
Holland, Peter W. H.