title: The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development.
abstract: Ligand-dependent activation, γ-secretase-processed cleavage, and recombining binding protein Jk (RBPj)-mediated downstream transcriptional activities of Notch receptors constitute the "canonical" Notch signaling pathway, which is essential for skin organogenesis. However, in Msx2-Cre mice, keratinocyte-specific deletion of the Rbpj gene in utero produced a significantly milder phenotype than either global Notch or γ-secretase loss. Herein, we investigated the underlying mechanisms for this apparent noncanonical signal using mouse genetics. We found no evidence that ligand back-signaling contributed to skin organogenesis. The perdurance of RBPj protein did not establish an epigenetic memory of a canonical signal in the youngest epidermal stem cells, and Notch targets were not derepressed. We provide evidence that γ-secretase-dependent but RBPj-independent Notch intracellular domain activity operating in the first hair follicles is responsible for a delay in follicular destruction, which results in lower serum thymic stromal lymphopoietin levels, milder B-cell lymphoproliferative disease, and improved survival in Msx2-Cre(+/tg);Rbpj(f/f) mice. Minimal amounts of the Notch intracellular domain were sufficient for rescue, which was not mediated by transcription, suggesting that the Notch intracellular domain is acting through a novel mechanism.
authors.affiliation: Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Turkoz
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, USA. Electronic address: Raphael.Kopan@cchmc.org.
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006197:Hair / Q000254:growth & development*; D018859:Hair Follicle / Q000196:embryology*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D051880:Receptors, Notch / Q000235:genetics*; D012380:Role; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch