Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA.
Endocrinology. 2023 Jan 9;164(3). doi: 10.1210/endocr/bqad016.
Epithelial to mesenchymal transition (EMT) is important for many developing organs, and for wound healing, fibrosis, and cancer. Pituitary stem cells undergo an EMT-like process as they migrate and initiate differentiation, but little is known about the input of signaling pathways or the genetic hierarchy of the transcriptional cascade. Prop1 mutant stem cells fail to undergo changes in cellular morphology, migration, and transition to the Pou1f1 lineage. We used Prop1 mutant mice to identify the changes in gene expression that are affiliated with EMT-like processes. BMP and TGF-β family gene expression was reduced in Prop1 mutants and Elf5, a transcription factor that characteristically suppresses EMT, had elevated expression. Genes involved in cell-cell contact such as cadherins and claudins were elevated in Prop1 mutants. To establish the genetic hierarchy of control, we manipulated gene expression in pituitary stem cell colonies. We determined that the EMT inducer, Zeb2, is necessary for robust BMP signaling and repression of Elf5. We demonstrated that inhibition of BMP signaling affects expression of target genes in the Id family, but it does not affect expression of other EMT genes. Zeb2 is necessary for expression of the SHH effector gene Gli2. However, knock down of Gli2 has little effect on the EMT-related genes, suggesting that it acts through a separate pathway. Thus, we have established the genetic hierarchy involved in the transition of pituitary stem cells to differentiation.
上皮间质转化（EMT）对于许多发育中的器官以及伤口愈合、纤维化和癌症都很重要。垂体干细胞在迁移和启动分化时会经历类似 EMT 的过程，但对于信号通路的输入或转录级联的遗传层次结构知之甚少。Prop1 突变干细胞无法改变细胞形态、迁移并向 Pou1f1 谱系转化。我们使用 Prop1 突变小鼠来鉴定与 EMT 样过程相关的基因表达变化。Prop1 突变体中 BMP 和 TGF-β 家族基因表达减少，而特征性抑制 EMT 的转录因子 Elf5 表达升高。Prop1 突变体中细胞间接触相关基因，如钙粘蛋白和紧密连接蛋白，表达升高。为了确定控制的遗传层次结构，我们在垂体干细胞集落中操纵基因表达。我们确定 EMT 诱导剂 Zeb2 对于强烈的 BMP 信号和 Elf5 的抑制是必需的。我们证明抑制 BMP 信号会影响 Id 家族靶基因的表达，但不会影响其他 EMT 基因的表达。Zeb2 是 SHH 效应基因 Gli2 表达所必需的。然而，Gli2 的敲低对 EMT 相关基因几乎没有影响，这表明它通过单独的途径起作用。因此，我们已经建立了垂体干细胞向分化过渡所涉及的遗传层次结构。
