Institute of Developmental Biology, University of Cologne, Cologne, Germany.
Cell Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
PLoS Genet. 2014 Jan;10(1):e1004048. doi: 10.1371/journal.pgen.1004048. Epub 2014 Jan 9.
p63 is a multi-isoform member of the p53 family of transcription factors. There is compelling genetic evidence that ΔNp63 isoforms are needed for keratinocyte proliferation and stemness in the developing vertebrate epidermis. However, the role of TAp63 isoforms is not fully understood, and TAp63 knockout mice display normal epidermal development. Here, we show that zebrafish mutants specifically lacking TAp63 isoforms, or p53, display compromised development of breeding tubercles, epidermal appendages which according to our analyses display more advanced stratification and keratinization than regular epidermis, including continuous desquamation and renewal of superficial cells by derivatives of basal keratinocytes. Defects are further enhanced in TAp63/p53 double mutants, pointing to partially redundant roles of the two related factors. Molecular analyses, treatments with chemical inhibitors and epistasis studies further reveal the existence of a linear TAp63/p53->Notch->caspase 3 pathway required both for enhanced proliferation of keratinocytes at the base of the tubercles and their subsequent differentiation in upper layers. Together, these studies identify the zebrafish breeding tubercles as specific epidermal structures sharing crucial features with the cornified mammalian epidermis. In addition, they unravel essential roles of TAp63 and p53 to promote both keratinocyte proliferation and their terminal differentiation by promoting Notch signalling and caspase 3 activity, ensuring formation and proper homeostasis of this self-renewing stratified epithelium.
p63 是 p53 转录因子家族的多异构体成员。有确凿的遗传证据表明，ΔNp63 异构体对于脊椎动物表皮的角质形成细胞增殖和干细胞特性是必需的。然而，TAp63 异构体的作用尚未完全了解，并且 TAp63 敲除小鼠表现出正常的表皮发育。在这里，我们显示特异性缺乏 TAp63 异构体或 p53 的斑马鱼突变体显示繁殖结节的发育受损，表皮附属物根据我们的分析显示比普通表皮具有更先进的分层和角化，包括由基底角质形成细胞的衍生物进行连续的脱屑和表面细胞的更新。在 TAp63/p53 双突变体中，缺陷进一步增强，表明这两个相关因素具有部分冗余作用。分子分析、化学抑制剂处理和上位性研究进一步揭示了 TAp63/p53->Notch->caspase 3 通路的存在，该通路对于结节底部角质形成细胞的增殖及其随后在上层的分化都是必需的。总之，这些研究将斑马鱼繁殖结节确定为具有与哺乳动物角质化表皮关键特征的特定表皮结构。此外，它们揭示了 TAp63 和 p53 的重要作用，通过促进 Notch 信号和 caspase 3 活性来促进角质形成细胞的增殖及其终末分化，从而确保这种自我更新的分层上皮的形成和适当的动态平衡。
