Notch at Implantation

Implantation of the blastocyst involves numerous hormonal and cellular factors with Notch playing a key role, according to a new study suggesting that this developmental regulator may help modulate expression of the progesterone receptor. In previous studies, Asgi Fazleabas and colleagues have shown that conditionally deleting Notch1 in the mouse uterus prevents decidualization, an event necessary for proper implantation. During decidualization, progesterone and estrogen set into motion changes in stromal cells of the endometrium that foster implantation. The researchers’ previous studies also suggest that NOTCH1 promotes decidualization in primates. What’s more, NOTCH expression has been observed to be decreased in women with endometriosis, which impairs decidualization and contributes to infertility. Previous studies suggest that to complete decidualization, Notch must in turn be downregulated. In the new study [1], Fazleabas and colleagues explored this idea by genetically manipulating Notch in the reproductive tract of the mouse to generate high levels of activity. They observed that there was no implantation. This phenotype could be due to a variety of defects—for instance, the mice had no uterine glands, structures that secrete a variety of substances that promote embryo implantation, and the animals also had low serum levels of progesterone. The reproductive tissues also showed only low levels of expression of the progesterone receptor, a phenotype that the researchers explored further. The mice, it appeared, had elevated levels of PU.1, a transcription factor thought to be a direct target of Notch. The researchers provide evidence that PU.1 interacts with a DNA methyltransferase that directs silencing of the gene encoding the progesterone receptor. Elevated levels of Notch signaling in the mice seemed to induce DNA methylation at the gene encoding the progesterone receptor. These findings provide insight into the regulation of decidualization and may have relevance for some reproductive disorders; endometriosis, for instance, can be accompanied by the hypermethylation of the gene encoding the progesterone receptor.