Dataset Information

Atrophin-Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR.

ABSTRACT: The evolutionarily conserved Hedgehog (Hh) signaling pathway is transduced by the Cubitus interruptus (Ci)/Gli family of transcription factors that exist in two distinct repressor (Ci(R)/Gli(R)) and activator (Ci(A)/Gli(A)) forms. Aberrant activation of Hh signaling is associated with various human cancers, but the mechanism through which Ci(R)/Gli(R) properly represses target gene expression is poorly understood. Here, we used Drosophila melanogaster and zebrafish models to define a repressor function of Atrophin (Atro) in Hh signaling. Atro directly bound to Ci through its C terminus. The N terminus of Atro interacted with a histone deacetylase, Rpd3, to recruit it to a Ci-binding site at the decapentaplegic (dpp) locus and reduce dpp transcription through histone acetylation regulation. The repressor function of Atro in Hh signaling was dependent on Ci. Furthermore, Rerea, a homologue of Atro in zebrafish, repressed the expression of Hh-responsive genes. We propose that the Atro-Rpd3 complex plays a conserved role to function as a Ci(R) corepressor.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC3840934 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Atrophin-Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR.

Zhang Zhao Z Feng Jing J Pan Chenyu C Lv Xiangdong X Wu Wenqing W Zhou Zhaocai Z Liu Feng F Zhang Lei L Zhao Yun Y

The Journal of cell biology 20131101 4

The evolutionarily conserved Hedgehog (Hh) signaling pathway is transduced by the Cubitus interruptus (Ci)/Gli family of transcription factors that exist in two distinct repressor (Ci(R)/Gli(R)) and activator (Ci(A)/Gli(A)) forms. Aberrant activation of Hh signaling is associated with various human cancers, but the mechanism through which Ci(R)/Gli(R) properly represses target gene expression is poorly understood. Here, we used Drosophila melanogaster and zebrafish models to define a repressor f ...[more]

PMID: 24385484

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Project description:Members of the Ski/Sno protein family are classified as proto-oncogenes and act as negative regulators of the TGF-ß/BMP-pathways in vertebrates and invertebrates. A newly identified member of this protein family is fussel (fuss), the Drosophila homologue of the human functional Smad suppressing elements (fussel-15 and fussel-18). We and others have shown that Fuss interacts with SMAD4 and that overexpression leads to a strong inhibition of Dpp signaling. However, to be able to characterize the endogenous Fuss function in Drosophila melanogaster, we have generated a number of state of the art tools including anti-Fuss antibodies, specific fuss-Gal4 lines and fuss mutant fly lines via the CRISPR/Cas9 system. Fuss is a predominantly nuclear, postmitotic protein, mainly expressed in interneurons and fuss mutants are fully viable without any obvious developmental phenotype. To identify potential target genes or cells affected in fuss mutants, we conducted targeted DamID experiments in adult flies, which revealed the function of fuss in bitter gustatory neurons. We fully characterized fuss expression in the adult proboscis and by using food choice assays we were able to show that fuss mutants display defects in detecting bitter compounds. This correlated with a reduction of gustatory receptor gene expression (Gr33a, Gr66a, Gr93a) providing a molecular link to the behavioral phenotype. In addition, Fuss interacts with Rpd3, and downregulation of rpd3 in gustatory neurons phenocopies the loss of Fuss expression. Surprisingly, there is no colocalization of Fuss with phosphorylated Mad in the larval central nervous system, excluding a direct involvement of Fuss in Dpp/BMP signaling. Here we provide a first and exciting link of Fuss function in gustatory bitter neurons. Although gustatory receptors have been well characterized, little is known regarding the differentiation and maturation of gustatory neurons. This work therefore reveals Fuss as a pivotal element for the proper differentiation of bitter gustatory neurons acting within a chromatin modifying complex.

Dataset Information

Atrophin-Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR.

Publications

Atrophin-Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR.

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