Division of Mammalian Development, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
Development. 2012 Dec 1;139(23):4365-73. doi: 10.1242/dev.083840.
In the developing lung, it is thought that the terminal buds of elongating airways contain a population of multipotent epithelial progenitors. As the bronchial tree extends, descendants of these cells give rise to lineage-restricted progenitors in the conducting airways via Notch signaling, which is involved in the establishment of epithelial Clara, ciliated and pulmonary neuroendocrine (NE) cell populations. However, the precise molecular details of this selection process are still emerging. Our stepwise removal of the three Notch receptors from the developing lung epithelium reveals that, whereas Notch2 mediates the Clara/ciliated cell fate decision with negligible contributions from Notch1 and Notch3, all three Notch receptors contribute in an additive manner to regulate the abundance of NE cells and the size of the presumptive pulmonary neuroepithelial body (pNEB) as a result of mutual interactions between NE cells and the Notch-dependent, SSEA-1(+), CC10(-) cell population surrounding the pNEB (SPNC cells). Ectopic expression of the Notch1 or Notch2 intracellular domain was sufficient to induce SSEA-1(+) cells and to suppress pNEB formation without expending Clara cells. We provide evidence that the additive functions of Notch receptors, together with other signaling pathways, maintains the expression of Hes1, a key regulator of NE cell fate, and that maintenance of Hes1 expression in epithelial cells is key to the regulation of pNEB size. These results suggest that two different assemblies of Notch receptors coordinate the numbers and distribution of the major epithelial cell types in the conducting airway during lung organogenesis.
在发育中的肺中，人们认为伸长气道的终末芽含有一群多能上皮祖细胞。随着支气管树的延伸，这些细胞的后代通过 Notch 信号通路在传导气道中产生谱系受限的祖细胞，Notch 信号通路参与了上皮 Clara 细胞、纤毛细胞和肺神经内分泌 (NE) 细胞群的建立。然而，这种选择过程的确切分子细节仍在不断涌现。我们逐步从发育中的肺上皮细胞中去除三个 Notch 受体，结果表明，Notch2 介导 Clara/纤毛细胞命运决定，Notch1 和 Notch3 的贡献可以忽略不计，而所有三个 Notch 受体都通过相互作用以附加的方式调节 NE 细胞的丰度和假定的肺神经上皮体 (pNEB) 的大小，这种相互作用发生在 NE 细胞和 Notch 依赖性、SSEA-1(+)、CC10(-)细胞群之间，该细胞群围绕着 pNEB (SPNC 细胞)。Notch1 或 Notch2 细胞内结构域的异位表达足以诱导 SSEA-1(+)细胞，并抑制 pNEB 的形成，而不会消耗 Clara 细胞。我们提供的证据表明，Notch 受体的附加功能与其他信号通路一起维持了 NE 细胞命运的关键调节因子 Hes1 的表达，上皮细胞中 Hes1 的表达维持是调节 pNEB 大小的关键。这些结果表明，两个不同的 Notch 受体组装协调了肺器官发生过程中传导气道中主要上皮细胞类型的数量和分布。
