The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage.
We previously determined that Notch2, and not Notch1, was required for forming proximal nephron segments. The dominance of Notch2 may be conserved in humans, since Notch2 mutations occur in Alagille syndrome (ALGS) 2 patients, which includes renal complications. To test whether mutations in Notch1 could increase the severity of renal complications in ALGS, we inactivated conditional Notch1 and Notch2 alleles in mice using a Six2-GFP::Cre. This BAC transgene is expressed mosaically in renal epithelial progenitors but uniformly in cells exiting the progenitor pool to undergo mesenchymal-to-epithelial transition. Although delaying Notch2 inactivation had a marginal effect on nephron numbers, it created a sensitized background in which the inactivation of Notch1 severely compromised nephron formation, function, and survival. These and additional observations indicate that Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J-dependent manner. A significant implication is that elevating Notch1 activity could improve renal functions in ALGS2 patients. As proof of principle, we determined that conditional inactivation of Mint, an inhibitor of Notch-RBP-J interaction, resulted in a moderate rescue of Notch2 null kidneys, implying that temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients.
Surendran
Kameswaran
K
Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Boyle
Scott
S
Barak
Hila
H
Kim
Mijin
M
Stomberski
Colin
C
McCright
Brent
B
Kopan
Raphael
R
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009030:Mosaicism; D009399:Nephrons / Q000196:embryology* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D019076:Transgenes / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C513072:Apba1 protein, mouse; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009419:Nerve Tissue Proteins; C497765:Notch2 protein, mouse; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D012097:Repressor Proteins; C497420:Six2 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases