Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
Development. 2009 Dec;136(24):4099-110. doi: 10.1242/dev.041582. Epub 2009 Nov 11.
The homeodomain transcription factors Cdx1, Cdx2 and Cdx4 play essential roles in anteroposterior vertebral patterning through regulation of Hox gene expression. Cdx2 is also expressed in the trophectoderm commencing at E3.5 and plays an essential role in implantation, thus precluding assessment of the cognate-null phenotype at later stages. Cdx2 homozygous null embryos generated by tetraploid aggregation exhibit an axial truncation indicative of a role for Cdx2 in elaborating the posterior embryo through unknown mechanisms. To better understand such roles, we developed a conditional Cdx2 floxed allele in mice and effected temporal inactivation at post-implantation stages using a tamoxifen-inducible Cre. This approach yielded embryos that were devoid of detectable Cdx2 protein and exhibited the axial truncation phenotype predicted from previous studies. This phenotype was associated with attenuated expression of genes encoding several key players in axial elongation, including Fgf8, T, Wnt3a and Cyp26a1, and we present data suggesting that T, Wnt3a and Cyp26a1 are direct Cdx2 targets. We propose a model wherein Cdx2 functions as an integrator of caudalizing information by coordinating axial elongation and somite patterning through Hox-independent and -dependent pathways, respectively.
同源域转录因子 Cdx1、Cdx2 和 Cdx4 通过调节 Hox 基因表达在前后椎体模式形成中发挥重要作用。Cdx2 也在 E3.5 开始时在滋养外胚层中表达，并在植入中发挥重要作用，因此排除了在稍后阶段评估同源缺失表型的可能性。通过四倍体聚集产生的 Cdx2 纯合缺失胚胎表现出轴向截断，表明 Cdx2 通过未知机制在通过尾部胚胎中发挥作用。为了更好地理解这些作用，我们在小鼠中开发了一种条件性 Cdx2 基因敲除等位基因，并使用他莫昔芬诱导型 Cre 在植入后阶段进行时间失活。这种方法产生的胚胎缺乏可检测到的 Cdx2 蛋白，并表现出先前研究预测的轴向截断表型。这种表型与编码几个关键轴向伸长基因的表达减弱有关，包括 Fgf8、T、Wnt3a 和 Cyp26a1，我们提供的数据表明 T、Wnt3a 和 Cyp26a1 是 Cdx2 的直接靶基因。我们提出了一个模型，其中 Cdx2 通过分别通过独立于 Hox 的和依赖于 Hox 的途径协调轴向伸长和体节模式形成，作为尾部化信息的整合者发挥作用。
