Document Detail


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.
MedLine Citation:
PMID:  19914235     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kameswaran Surendran; Scott Boyle; Hila Barak; Mijin Kim; Colin Stomberski; Brent McCright; Raphael Kopan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-11-13
Journal Detail:
Title:  Developmental biology     Volume:  337     ISSN:  1095-564X     ISO Abbreviation:  Dev. Biol.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-27     Completed Date:  2010-02-25     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0372762     Medline TA:  Dev Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  386-95     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Survival
Epithelial Cells / cytology,  metabolism
Gene Dosage / genetics*
Green Fluorescent Proteins / metabolism
Homeodomain Proteins / metabolism
Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
Integrases / metabolism
Kidney Glomerulus / cytology,  metabolism
Kidney Tubules, Proximal / cytology,  metabolism
Mesoderm / cytology,  metabolism
Mice
Mosaicism
Nephrons / embryology*,  metabolism*
Nerve Tissue Proteins / metabolism*
Paired Box Transcription Factors / metabolism
Receptor, Notch1 / metabolism*
Receptor, Notch2 / metabolism
Repressor Proteins / metabolism
Stem Cells / cytology,  metabolism
Transcription Factors / metabolism
Transcription, Genetic
Transgenes / genetics
Grant Support
ID/Acronym/Agency:
5P30DK07933/DK/NIDDK NIH HHS; 5T32DK007126/DK/NIDDK NIH HHS; P30 CA091842/CA/NCI NIH HHS; P30 CA091842-03/CA/NCI NIH HHS; P30 CA91842/CA/NCI NIH HHS; P30 DK052574-10/DK/NIDDK NIH HHS; P30 DK079333/DK/NIDDK NIH HHS; P30 DK079333-03/DK/NIDDK NIH HHS; P30DK052574/DK/NIDDK NIH HHS; R01 DK066408/DK/NIDDK NIH HHS; R01 DK066408-05/DK/NIDDK NIH HHS; R01 DK066408-06/DK/NIDDK NIH HHS; T32 DK007126/DK/NIDDK NIH HHS; T32 DK007126-31/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Apba1 protein, mouse; 0/Homeodomain Proteins; 0/Immunoglobulin J Recombination Signal Sequence-Binding Protein; 0/Nerve Tissue Proteins; 0/Notch2 protein, mouse; 0/Paired Box Transcription Factors; 0/Rbpj protein, mouse; 0/Receptor, Notch1; 0/Receptor, Notch2; 0/Repressor Proteins; 0/Six2 protein, mouse; 0/Transcription Factors; 138016-91-8/Pax3 protein, mouse; 147336-22-9/Green Fluorescent Proteins; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases
Comments/Corrections

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