Diencephalic defects underlie an array of neurological diseases. Previous studies have suggested that retinoic acid (RA) signaling is involved in diencephalic development at late stages of embryonic development, but its roles and mechanisms of action during early neural development are still unclear. Here we demonstrate that mice lacking enzymatic activity of the acetyltransferase GCN5 ((Gcn5hat/hat )), which were previously characterized with respect to their exencephalic phenotype, exhibit significant diencephalic expansion, decreased diencephalic RA signaling, and increased diencephalic WNT and SHH signaling. Using a variety of molecular biology techniques in both cultured neuroepithelial cells treated with a GCN5 inhibitor and forebrain tissue from (Gcn5hat/hat ) embryos, we demonstrate that GCN5, RARα/γ, and the poorly characterized protein TACC1 form a complex in the nucleus that binds specific retinoic acid response elements in the absence of RA. Furthermore, RA triggers GCN5-mediated acetylation of TACC1, which results in dissociation of TACC1 from retinoic acid response elements and leads to transcriptional activation of RA target genes. Intriguingly, RA signaling defects caused by in vitro inhibition of GCN5 can be rescued through RA-dependent mechanisms that require RARβ. Last, we demonstrate that the diencephalic expansion and transcriptional defects seen in (Gcn5hat/hat ) mutants can be rescued with gestational RA supplementation, supporting a direct link between GCN5, TACC1, and RA signaling in the developing diencephalon. Together, our studies identify a novel, nonhistone substrate for GCN5 whose modification regulates a previously undescribed, tissue-specific mechanism of RA signaling that is required to restrict diencephalic size during early forebrain development.SIGNIFICANCE STATEMENT Changes in diencephalic size and shape, as well as SNPs associated with retinoic acid (RA) signaling-associated genes, have been linked to neuropsychiatric disorders. However, the mechanisms that regulate diencephalic morphogenesis and the involvement of RA signaling in this process are poorly understood. Here we demonstrate a novel role of the acetyltransferase GCN5 in a previously undescribed mechanism of RA signaling in the developing forebrain that is required to maintain the appropriate size of the diencephalon. Together, our experiments identify a novel nonhistone substrate of GCN5, highlight an essential role for both GCN5 and RA signaling in early diencephalic development, and elucidate a novel molecular regulatory mechanism for RA signaling that is specific to the developing forebrain.
Pubmed ID: 28154153 RIS Download
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This polyclonal secondary targets IgG
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View all literature mentionsThis monoclonal targets Recombinant full length rat MASH1 protein
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets Raised against peptide mapping to the carboxy terminus
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View all literature mentionsThis monoclonal targets LEF1 (C12A5) Rabbit mAb
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View all literature mentionsThis polyclonal targets RARA
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View all literature mentionsThis unknown targets Mouse IgG (H+L)
View all literature mentionsThis polyclonal targets TACC1 N-Terminal antibody produced in rabbit
View all literature mentionsThis monoclonal targets Nkx2.2 transcription factor
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsCell line NE-4C is a Spontaneously immortalized cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets IgG (H+L)
View all literature mentionsThis monoclonal targets Olig2
View all literature mentionsThis monoclonal targets Nkx2.2 transcription factor
View all literature mentionsThis polyclonal targets Mouse TBR2 / Eomes
View all literature mentionsThis monoclonal targets Recombinant full length rat MASH1 protein
View all literature mentionsThis monoclonal targets LEF1 (C12A5) Rabbit mAb
View all literature mentionsThis polyclonal targets FOXG1
View all literature mentionsThis polyclonal targets RARA
View all literature mentionsThis monoclonal targets GCN5L2
View all literature mentionsThis monoclonal targets Raised against peptide mapping to the carboxy terminus
View all literature mentionsThis monoclonal targets RpII215
View all literature mentionsThis monoclonal targets beta-Tubulin
View all literature mentionsThis polyclonal targets TACC1 N-Terminal antibody produced in rabbit
View all literature mentionsThis polyclonal secondary targets not applicable
View all literature mentionsThis polyclonal targets Acetylated-Lysine
View all literature mentionsThis polyclonal secondary targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis unknown targets Mouse IgG (H+L)
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
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