Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108, Freiburg, Germany.
Sci Rep. 2017 Aug 17;7(1):8492. doi: 10.1038/s41598-017-09213-1.
Thymopoiesis strictly depends on the function of the Foxn1 transcription factor that is expressed in the thymic epithelium. During embryonic development, initial expression of the Foxn1 gene is induced in the pharyngeal endoderm by mesenchyme-derived BMP4 signals. Here, by engineering a time-delayed feedback system of BMP inhibition in mouse embryos, we demonstrate that thymopoiesis irreversibly fails if Foxn1 gene expression does not occur during a defining time span in mid-gestation. We also reveal an epistatic interaction between the extent of BMP signalling and the gene dosage of Foxn1. Our findings illustrate the complexities of the early steps of thymopoiesis and indicate that sporadic forms of thymic hypoplasia in humans may result from the interaction of genes affecting the magnitude of BMP signalling and Foxn1 expression.
胸腺发生严格依赖于 Foxn1 转录因子的功能，该转录因子在胸腺上皮细胞中表达。在胚胎发育过程中，Foxn1 基因的初始表达是由中胚层衍生的 BMP4 信号诱导咽内胚层产生的。在这里，通过构建小鼠胚胎中 BMP 抑制的时滞反馈系统，我们证明如果 Foxn1 基因表达不在中孕期的一个特定时间段内发生，那么胸腺发生就会不可逆转地失败。我们还揭示了 BMP 信号的程度和 Foxn1 基因剂量之间的上位性相互作用。我们的发现说明了胸腺发生早期步骤的复杂性，并表明人类散发性胸腺发育不全可能是由于影响 BMP 信号和 Foxn1 表达幅度的基因相互作用的结果。
