title: An F-domain introduced by alternative splicing regulates activity of the zebrafish thyroid hormone receptor alpha.
abstract: Thyroid hormones (THs) play an important role in vertebrate development; however, the underlying mechanisms of their actions are still poorly understood. Zebrafish (Danio rerio) is an emerging vertebrate model system to study the roles of THs during development. In general, the response to THs relies on closely related proteins and mechanisms across vertebrate species, however some species-specific differences exist. In contrast to mammals, zebrafish has two TRalpha genes (thraa, thrab). Moreover, the zebrafish thraa gene expresses a TRalpha isoform (TRalphaA1) that differs from other TRs by containing additional C-terminal amino acids. C-terminal extensions, called "F domains", are common in other members of the nuclear receptor superfamily and modulate the response of these receptors to hormones. Here we demonstrate that the F-domain constrains the transcriptional activity of zebrafish TRalpha by altering the selectivity of this receptor for certain coactivator binding motifs. We found that the F-domain of zebrafish TRalphaA1 is encoded on a separate exon whose inclusion is regulated by alternative splicing, indicating a regulatory role of the F-domain in vivo. Quantitative expression analyses revealed that TRalphaA1 is primarily expressed in reproductive organs whereas TRalphaB and the TRalphaA isoform that lacks the F-domain (TRalphaA1-2) appear to be ubiquitous. The relative expression levels of these TRalpha transcripts differ in a tissue-specific manner suggesting that zebrafish uses both alternative splicing and differential expression of TRalpha genes to diversify the cellular response to THs.
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takayama
authors.forename: Ute
authors.initials: U
authors.lastname: Hostick
authors.forename: Melissa
authors.initials: M
authors.lastname: Haendel
authors.forename: Judith
authors.initials: J
authors.lastname: Eisen
authors.forename: Beatrice
authors.initials: B
authors.lastname: Darimont
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D004625:Embryo, Nonmammalian; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology*; D015533:Transcriptional Activation; D015027:Zebrafish / Q000235:genetics*
chemical_list: D037021:Thyroid Hormone Receptors alpha