title: Non-cell-autonomous retinoid signaling is crucial for renal development.
abstract: In humans and mice, mutations in the Ret gene result in Hirschsprung's disease and renal defects. In the embryonic kidney, binding of Ret to its ligand, Gdnf, induces a program of epithelial cell remodeling that controls primary branch formation and branching morphogenesis within the kidney. Our previous studies showed that transcription factors belonging to the retinoic acid (RA) receptor family are crucial for controlling Ret expression in the ureteric bud; however, the mechanism by which retinoid-signaling acts has remained unclear. In the current study, we show that expression of a dominant-negative RA receptor in mouse ureteric bud cells abolishes Ret expression and Ret-dependent functions including ureteric bud formation and branching morphogenesis, indicating that RA-receptor signaling in ureteric bud cells is crucial for renal development. Conversely, we find that RA-receptor signaling in ureteric bud cells depends mainly on RA generated in nearby stromal cells by retinaldehyde dehydrogenase 2, an enzyme required for most fetal RA synthesis. Together, these studies suggest that renal development depends on paracrine RA signaling between stromal mesenchyme and ureteric bud cells that regulates Ret expression both during ureteric bud formation and within the developing collecting duct system.
authors.affiliation: Department of Urology, Columbia University, New York, New York 10032 USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Rosselot
authors.forename: Lee
authors.initials: L
authors.lastname: Spraggon
authors.forename: Ian
authors.initials: I
authors.lastname: Chia
authors.forename: Ekatherina
authors.initials: E
authors.lastname: Batourina
authors.forename: Paul
authors.initials: P
authors.lastname: Riccio
authors.forename: Benson
authors.initials: B
authors.lastname: Lu
authors.forename: Karen
authors.initials: K
authors.lastname: Niederreither
authors.forename: Pascal
authors.initials: P
authors.lastname: Dolle
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Frank
authors.initials: F
authors.lastname: Costantini
authors.forename: Thierry
authors.initials: T
authors.lastname: Gilbert
authors.forename: Andrei
authors.initials: A
authors.lastname: Molotkov
authors.forename: Cathy
authors.initials: C
authors.lastname: Mendelsohn
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D006801:Humans; D007120:Immunochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology*; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009924:Organ Culture Techniques; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000502:physiology; D012176:Retinoids / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D012176:Retinoids; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse; D050697:Retinal Dehydrogenase; C508905:retinaldehyde dehydrogenase 3, mouse