title: Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse.
abstract: Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free-floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie differentiation into the decidual phenotype remain largely undefined. The Notch family of transmembrane receptors transduce extracellular signals responsible for cell survival, cell-to-cell communication, and differentiation, all fundamental processes for decidualization and pregnancy. Using a murine artificial decidualization model, pharmacological inhibition of Notch signaling by γ-secretase inhibition resulted in a significantly decreased deciduoma. Furthermore, a progesterone receptor (PR)-Cre Notch1 bigenic (Notch1(d/d)) confirmed a Notch1-dependent hypomorphic decidual phenotype. Microarray and pathway analysis, following Notch1 ablation, demonstrated significantly altered signaling repertoire. Concomitantly, hierarchical clustering demonstrated Notch1-dependent differences in gene expression. Uteri deprived of Notch1 signaling demonstrated decreased cellular proliferation; namely, reduced proliferation-specific antigen, Ki67, altered p21, cdk6, and cyclinD activity and an increased apoptotic-profile, cleaved caspase-3, Bad, and attenuated Bcl2. The results demonstrate that the preimplantation uterus relies on Notch signaling to inhibit apoptosis of stromal fibroblasts and regulate cell cycle progression, which together promotes successful decidualization. In summary, Notch1 signaling modulates multiple signaling mechanisms crucial for decidualization and these studies provide additional perspectives to the coordination of multiple signaling modalities required during decidualization.
authors: Department of Physiology and Biophysics, University of Illinois, Chicago, IL, USA.
authors: Yalda
authors: Y
authors: Afshar
authors: Jae-Wook
authors: JW
authors: Jeong
authors: Damian
authors: D
authors: Roqueiro
authors: Franco
authors: F
authors: DeMayo
authors: John
authors: J
authors: Lydon
authors: Freddy
authors: F
authors: Radtke
authors: Rachel
authors: R
authors: Radnor
authors: Lucio
authors: L
authors: Miele
authors: Asgerally
authors: A
authors: Fazleabas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000502:physiology*; D010064:Embryo Implantation / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1