title: miRNAs control tracheal chondrocyte differentiation.
abstract: The specific program that enables the stereotypic differentiation of specialized cartilages, including the trachea, is intrinsically distinct from the program that gives rise to growth plate hypertrophic chondrocytes. For example, Snail1 is an effector of FGF signaling in growth plate pre-hypertrophic chondrocytes, but it derails the normal program of permanent chondrocytes, repressing the transcription of Aggrecan and Collagen type 2a1 (Col2a1). Here we show that miRNA activity is essential for normal trachea development and that miR-125b and miR-30a/c keep Snail1 at low levels, thus enabling full functional differentiation of Col2a1 tracheal chondrocytes. Specific inhibition of miR-125b and miR-30a/c in chondrocytes or Dicer1 knockout in the trachea, de-repress Snail1. As a consequence, the transcription of Aggrecan and Col2a1 is hampered and extracellular matrix deposition is decreased. Our data reveals a new miRNA pathway that is safekeeping the specific genetic program of differentiated and matrix-producing tracheal chondrocytes from acquisition of unwanted signals. This pathway may improve understanding of human primary tracheomalacia and improve protocols for cartilage tissue engineering.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Israel
authors.forename: Ben
authors.initials: B
authors.lastname: Gradus
authors.forename: Ilana
authors.initials: I
authors.lastname: Alon
authors.forename: Eran
authors.initials: E
authors.lastname: Hornstein
mesh_terms: D020413:3' Untranslated Regions; D053674:Aggrecans / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D020219:Chondrogenesis / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000209:etiology / Q000235:genetics; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014132:Trachea / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D053674:Aggrecans; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases