Snitow Melinda E, Li Shanru, Morley Michael P, Rathi Komal, Lu Min Min, Kadzik Rachel S, Stewart Kathleen M, Morrisey Edward E
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Development. 2015 Jan 1;142(1):108-17. doi: 10.1242/dev.116947.
The development of the lung epithelium is regulated in a stepwise fashion to generate numerous differentiated and stem cell lineages in the adult lung. How these different lineages are generated in a spatially and temporally restricted fashion remains poorly understood, although epigenetic regulation probably plays an important role. We show that the Polycomb repressive complex 2 component Ezh2 is highly expressed in early lung development but is gradually downregulated by late gestation. Deletion of Ezh2 in early lung endoderm progenitors leads to the ectopic and premature appearance of Trp63+ basal cells that extend the entire length of the airway. Loss of Ezh2 also leads to reduced secretory cell differentiation. In their place, morphologically similar cells develop that express a subset of basal cell genes, including keratin 5, but no longer express high levels of either Trp63 or of standard secretory cell markers. This suggests that Ezh2 regulates the phenotypic switch between basal cells and secretory cells. Together, these findings show that Ezh2 restricts the basal cell lineage during normal lung endoderm development to allow the proper patterning of epithelial lineages during lung formation.
肺上皮的发育以逐步方式受到调控，从而在成年肺中产生众多分化的和干细胞谱系。尽管表观遗传调控可能起着重要作用，但对于这些不同谱系如何在空间和时间上受到限制的方式产生，人们仍然知之甚少。我们发现，多梳抑制复合物2组分Ezh2在肺发育早期高度表达，但在妊娠晚期逐渐下调。在肺内胚层祖细胞早期缺失Ezh2会导致Trp63+基底细胞异位和过早出现，这些基底细胞延伸至气道的全长。Ezh2的缺失还导致分泌细胞分化减少。取而代之的是，发育出形态相似的细胞，这些细胞表达包括角蛋白5在内的基底细胞基因子集，但不再高表达Trp63或标准分泌细胞标志物。这表明Ezh2调节基底细胞和分泌细胞之间的表型转换。总之，这些发现表明，Ezh2在正常肺内胚层发育过程中限制基底细胞谱系，以允许在肺形成过程中上皮谱系的正确模式化。
