title: Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis.
abstract: MicroRNAs, activated by the enzyme Dicer1, control post-transcriptional gene expression. Dicer1 has important roles in the epithelium during nephrogenesis, but its function in stromal cells during kidney development is unknown. To study this, we inactivated Dicer1 in renal stromal cells. This resulted in hypoplastic kidneys, abnormal differentiation of the nephron tubule and vasculature, and perinatal mortality. In mutant kidneys, genes involved in stromal cell migration and activation were suppressed as were those involved in epithelial and endothelial differentiation and maturation. Consistently, polarity of the proximal tubule was incorrect, distal tubule differentiation was diminished, and elongation of Henle's loop attenuated resulting in lack of inner medulla and papilla in stroma-specific Dicer1 mutants. Glomerular maturation and capillary loop formation were abnormal, whereas peritubular capillaries, with enhanced branching and increased diameter, formed later. In Dicer1-null renal stromal cells, expression of factors associated with migration, proliferation, and morphogenic functions including α-smooth muscle actin, integrin-α8, -β1, and the WNT pathway transcriptional regulator LEF1 were reduced. Dicer1 mutation in stroma led to loss of expression of distinct microRNAs. Of these, miR-214, -199a-5p, and -199a-3p regulate stromal cell functions ex vivo, including WNT pathway activation, migration, and proliferation. Thus, Dicer1 activity in the renal stromal compartment regulates critical stromal cell functions that, in turn, regulate differentiation of the nephron and vasculature during nephrogenesis.
authors: Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA.
authors: Naoki
authors: N
authors: Nakagawa
authors: Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA.
authors: Cuiyan
authors: C
authors: Xin
authors: 1] Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA [2] Research and Development, Biogen Idec, Cambridge, Massachusetts, USA.
authors: Allie M
authors: AM
authors: Roach
authors: Department of Medicine, Division of Nephrology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Natalie
authors: N
authors: Naiman
authors: 1] Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA [2] Kidney Research Institute, University of Washington, Seattle, Washington, USA.
authors: Stuart J
authors: SJ
authors: Shankland
authors: 1] Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA [2] Research and Development, Biogen Idec, Cambridge, Massachusetts, USA.
authors: Giovanni
authors: G
authors: Ligresti
authors: 1] Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA [2] Research and Development, Biogen Idec, Cambridge, Massachusetts, USA.
authors: Shuyu
authors: S
authors: Ren
authors: Research and Development, Biogen Idec, Cambridge, Massachusetts, USA.
authors: Suzanne
authors: S
authors: Szak
authors: 1] Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA [2] Research and Development, Biogen Idec, Cambridge, Massachusetts, USA.
authors: Ivan G
authors: IG
authors: Gomez
authors: 1] Division of Nephrology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington, USA [2] Research and Development, Biogen Idec, Cambridge, Massachusetts, USA [3] Kidney Research Institute, University of Washington, Seattle, Washington, USA [4] Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
authors: Jeremy S
authors: JS
authors: Duffield
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000196:embryology; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D039001:Integrin alpha Chains / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D007684:Kidney Tubules / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D007686:Kidney Tubules, Distal / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D007687:Kidney Tubules, Proximal / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D008138:Loop of Henle / Q000098:blood supply / Q000166:cytology / Q000196:embryology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009399:Nephrons / Q000002:abnormalities / Q000166:cytology / Q000196:embryology*; D038081:Organogenesis / Q000235:genetics; D050199:Podocytes / Q000502:physiology; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017154:Stromal Cells / Q000502:physiology; D059467:Transcriptome; D014513:Ureter / Q000002:abnormalities; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D000199:Actins; D039001:Integrin alpha Chains; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; C534781:Mirn214 microRNA, mouse; C544013:alpha-smooth muscle actin, mouse; C093856:integrin alpha8; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
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