title: Adam10 mediates the choice between principal cells and intercalated cells in the kidney.
abstract: A disintegrin and metalloproteinase domain 10 (Adam10), a member of the ADAM family of cell membrane-anchored proteins, has been linked to the regulation of the Notch, EGF, E-cadherin, and other signaling pathways. However, it is unclear what role Adam10 has in the kidney in vivo. In this study, we showed that Adam10 deficiency in ureteric bud (UB) derivatives leads to a decrease in urinary concentrating ability, polyuria, and hydronephrosis in mice. Furthermore, Adam10 deficiency led to a reduction in the percentage of aquaporin 2 (Aqp2)(+) principal cells (PCs) in the collecting ducts that was accompanied by a proportional increase in the percentage of intercalated cells (ICs). This increase was more prominent in type A ICs than in type B ICs. Foxi1, a transcription factor important for the differentiation of ICs, was upregulated in the Adam10 mutants. The observed reduction of Notch activity in Adam10 mutant collecting duct epithelium and the similar reduction of PC/IC ratios in the collecting ducts in mice deficient for mindbomb E3 ubiquitin protein ligase 1, a key regulator of the Notch and Wnt/receptor-like tyrosine kinase signaling pathways, suggest that Adam10 regulates cell fate determination through the activation of Notch signaling, probably through the regulation of Foxi1 expression. However, phenotypic differences between the Adam10 mutants, the Mib1 mutants, and the Foxi1 mutants suggest that the functions of Adam10 in determining the fate of collecting duct cells are more complex than those of a simple upstream factor in a linear pathway involving Notch and Foxi1.
authors.affiliation: Department of Medicine, Department of Cell Biology and Physiology, and Division of Pediatric Urology, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Qiusha
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Medicine, Department of Cell Biology and Physiology, and.
authors.forename: Yinqiu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Department of Cell Biology and Physiology, and.
authors.forename: Piyush
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: Department of Medicine, Department of Cell Biology and Physiology, and.
authors.forename: Kalyan R
authors.initials: KR
authors.lastname: Manda
authors.affiliation: Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota; and.
authors.forename: Malini
authors.initials: M
authors.lastname: Mukherjee
authors.affiliation: Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota; and.
authors.forename: Malay
authors.initials: M
authors.lastname: Chaklader
authors.affiliation: Division of Pediatric Urology, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Paul F
authors.initials: PF
authors.lastname: Austin
authors.affiliation: Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota; and Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota fchen@dom.wustl.edu kameswaran.surendran@sanfordhealth.org.
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Surendran
authors.affiliation: Department of Medicine, Department of Cell Biology and Physiology, and fchen@dom.wustl.edu kameswaran.surendran@sanfordhealth.org.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051399:Aquaporin 2 / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006869:Hydronephrosis / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011141:Polyuria / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D015820:Cadherins; D051858:Forkhead Transcription Factors; C099993:Foxl1 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: diabetes insipidus; genetics and development; renal tubular epithelial cells