title: Nuclear receptor corepressors Ncor1 and Ncor2 (Smrt) are required for retinoic acid-dependent repression of Fgf8 during somitogenesis.
abstract: Retinoic acid (RA) repression of Fgf8 is required for many different aspects of organogenesis, however relatively little is known about how endogenous RA controls gene repression as opposed to gene activation. Here, we show that nuclear receptor corepressors NCOR1 and NCOR2 (SMRT) redundantly mediate the ability of RA to repress Fgf8. Ncor1;Ncor2 double mutants generated by CRISPR/Cas9 gene editing exhibited a small somite and distended heart phenotype similar to that of RA-deficient Raldh2-/- embryos, associated with increased Fgf8 expression and FGF signaling in caudal progenitors and heart progenitors. Embryo chromatin immunoprecipitation studies revealed that NCOR1/2 but not coactivators are recruited to the Fgf8 RA response element (RARE) in an RA-dependent manner, whereas coactivators but not NCOR1/2 are recruited RA-dependently to a RARE near Rarb that is activated by RA. CRISPR/Cas9-mediated genomic deletion of the Fgf8 RARE in mouse embryos often resulted in a small somite defect with Fgf8 derepression caudally, but no defect was observed in heart development or heart Fgf8 expression. This suggests the existence of another DNA element whose function overlaps with the Fgf8 RARE to mediate Fgf8 repression by RA and NCOR1/2. Our studies support a model in which NCOR1/2 mediates direct RA-dependent repression of Fgf8 in caudal progenitors in order to control somitogenesis.
authors: Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors: Sandeep
authors: S
authors: Kumar
authors: Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors: Thomas J
authors: TJ
authors: Cunningham
authors: Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: duester@SBPdiscovery.org.
authors: Gregg
authors: G
authors: Duester
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D056970:Co-Repressor Proteins / Q000235:genetics; D047108:Embryonic Development; D051524:Fibroblast Growth Factor 8 / Q000037:antagonists & inhibitors*; D000072669:Gene Editing / Q000379:methods; D006321:Heart / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics*; D038081:Organogenesis / Q000235:genetics*; D015398:Signal Transduction; D019170:Somites / Q000002:abnormalities* / Q000196:embryology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; C496457:Fgf8 protein, mouse; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D051524:Fibroblast Growth Factor 8; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse
keywords: CRISPR/Cas9 gene editing; Caudal progenitors; Fgf8; NCOR; Nuclear receptor corepressor; Retinoic acid response element; SMRT; Somitogenesis