title: Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo.
abstract: Hox genes control many developmental events along the AP axis, but few target genes have been identified. Whether target genes are activated or repressed, what enhancer elements are required for regulation, and how different domains of the Hox proteins contribute to regulatory specificity are poorly understood. Six2 is genetically downstream of both the Hox11 paralogous genes in the developing mammalian kidney and Hoxa2 in branchial arch and facial mesenchyme. Loss-of-function of Hox11 leads to loss of Six2 expression and loss-of-function of Hoxa2 leads to expanded Six2 expression. Herein we demonstrate that a single enhancer site upstream of the Six2 coding sequence is responsible for both activation by Hox11 proteins in the kidney and repression by Hoxa2 in the branchial arch and facial mesenchyme in vivo. DNA-binding activity is required for both activation and repression, but differential activity is not controlled by differences in the homeodomains. Rather, protein domains N- and C-terminal to the homeodomain confer activation versus repression activity. These data support a model in which the DNA-binding specificity of Hox proteins in vivo may be similar, consistent with accumulated in vitro data, and that unique functions result mainly from differential interactions mediated by non-homeodomain regions of Hox proteins.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Yallowitz
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Gong
authors.forename: Ilea T
authors.initials: IT
authors.lastname: Swinehart
authors.forename: Lisa T
authors.initials: LT
authors.lastname: Nelson
authors.forename: Deneen M
authors.initials: DM
authors.lastname: Wellik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001934:Branchial Region / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C497420:Six2 protein, mouse; D014157:Transcription Factors; D004247:DNA; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases