TY - JOUR
T1 - The extracellular domain of notch2 increases its cell-surface abundance and ligand responsiveness during kidney development
AU - Liu, Zhenyi
AU - Chen, Shuang
AU - Boyle, Scott
AU - Zhu, Yu
AU - Zhang, Andrew
AU - Piwnica-Worms, David R.
AU - Ilagan, Ma Xenia G.
AU - Kopan, Raphael
N1 - Funding Information:
We thank the staffs of the Murine Embryonic Stem Cell Core, Mouse Genetics Core, and Siteman Flow Cytometry Core of the Siteman Cancer Center, Washington University, for their assistance. We thank Dr. MacDonald for providing unconjugated N1 and N2 antibodies, Dr. Groves for providing Lfng-GFP mice, and Dr. Blacklow for communicating unpublished results. We thank members of the Kopan laboratory for stimulating discussions and Mary Fulbright and Hila Barak for technical assistance. Z.L., S.C., S.B., A.Z., and R.K. were supported by the National Institute of Diabetes and Digestive and Kidney Disease (DK066408) and the National Institute of General Medicine (GM55479). M.X.G.I. and D.R.P.-W. were supported in part by the National Cancer Institute (CA094056).
PY - 2013/6/24
Y1 - 2013/6/24
N2 - Notch2, but not Notch1, plays indispensable roles in kidney organogenesis, and Notch2 haploinsufficiency is associated with Alagille syndrome. We proposed that proximal nephron fates are regulated by a threshold that requires nearly all available free Notch intracellular domains (NICDs) but could not identify the mechanism that explains why Notch2 (N2) is more important than Notch1 (N1). By generating mice that swap their ICDs, we establish that the overall protein concentration, expression domain, or ICD amino acid composition does not account for the differential requirement of these receptors. Instead, we find that the N2 extracellular domain (NECD) increases Notch protein localization to the cell surface during kidney development and is cleaved more efficiently upon ligand binding. This context-specific asymmetry in NICD release efficiency is further enhanced by Fringe. Our results indicate that an elevated N1 surface level could compensate for the loss of N2 signal in specific cell contexts
AB - Notch2, but not Notch1, plays indispensable roles in kidney organogenesis, and Notch2 haploinsufficiency is associated with Alagille syndrome. We proposed that proximal nephron fates are regulated by a threshold that requires nearly all available free Notch intracellular domains (NICDs) but could not identify the mechanism that explains why Notch2 (N2) is more important than Notch1 (N1). By generating mice that swap their ICDs, we establish that the overall protein concentration, expression domain, or ICD amino acid composition does not account for the differential requirement of these receptors. Instead, we find that the N2 extracellular domain (NECD) increases Notch protein localization to the cell surface during kidney development and is cleaved more efficiently upon ligand binding. This context-specific asymmetry in NICD release efficiency is further enhanced by Fringe. Our results indicate that an elevated N1 surface level could compensate for the loss of N2 signal in specific cell contexts
UR - http://www.scopus.com/inward/record.url?scp=84879532571&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2013.05.022
DO - 10.1016/j.devcel.2013.05.022
M3 - Article
C2 - 23806616
AN - SCOPUS:84879532571
SN - 1534-5807
VL - 25
SP - 585
EP - 598
JO - Developmental cell
JF - Developmental cell
IS - 6
ER -