Institute for Animal Developmental and Molecular Biology; Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
Dev Biol. 2010 Apr 15;340(2):256-68. doi: 10.1016/j.ydbio.2010.01.037. Epub 2010 Feb 6.
During embryogenesis, the Dkk1 mediated Wnt inhibition controls the spatiotemporal dynamics of cell fate determination, cell differentiation and cell death. Furthermore, the Dkk1 dose is critical for the normal Wnt homeostasis, as alteration of the Dkk1 activity is associated with various diseases. We investigated the regulation of Dkk1 expression during embryonic development. We identified nine conserved non-coding elements (CNEs), located 3' to the Dkk1 locus. Analyses of the regulatory potential revealed that four of these CNEs in combination drive reporter expression very similar to Dkk1 expression in several organs of transgenic embryos. We extended the knowledge of Dkk1 expression during hypophysis, external genitalia and kidney development, suggesting so far to unexplored functions of Dkk1 during the development of these organs. Characterization of the regulatory potential of four individual CNEs revealed that each of these promotes Dkk1 expression in brain and kidney. In combination, two enhancers are responsible for expression in the pituitary and the genital tubercle. Furthermore, individual CNEs mediates craniofacial, optic cup and limb specific Dkk1 regulation. Our study substantially improves the knowledge of Dkk1 regulation during embryonic development and thus might be of high relevance for therapeutic approaches.
在胚胎发生过程中，Dkk1 介导的 Wnt 抑制控制细胞命运决定、细胞分化和细胞死亡的时空动态。此外，Dkk1 的剂量对于正常的 Wnt 动态平衡至关重要，因为 Dkk1 活性的改变与各种疾病有关。我们研究了胚胎发育过程中 Dkk1 表达的调节。我们确定了 Dkk1 基因座 3'端的九个保守非编码元件 (CNEs)。对调节潜能的分析表明，这四个 CNE 结合在一起，驱动报告基因的表达与转基因胚胎几个器官中 Dkk1 的表达非常相似。我们扩展了 Dkk1 在垂体、外生殖器和肾脏发育过程中的表达知识，这表明在这些器官的发育过程中 Dkk1 具有迄今尚未探索的功能。对四个单独 CNE 的调节潜能的表征表明，这些 CNE 中的每一个都促进了大脑和肾脏中 Dkk1 的表达。两个增强子结合在一起负责垂体和生殖器结节的表达。此外，单个 CNE 介导颅面、视杯和肢体特异性 Dkk1 调节。我们的研究极大地提高了对胚胎发育过程中 Dkk1 调节的认识，因此可能对治疗方法具有重要意义。
