title: Secisbp2 is essential for embryonic development and enhances selenoprotein expression.
abstract: OBJECTIVE
  The selenocysteine insertion sequence (SECIS)-binding protein 2 (Secisbp2) binds to SECIS elements located in the 3'-untranslated region of eukaryotic selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes.
  
  
  RESULTS
  Unlike tRNA[Ser]Sec-deficient embryos, homozygous Secisbp2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of Secisbp2 reduced the amount of selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of Secisbp2 in hepatocytes significantly decreased selenoprotein expression. Unexpectedly, the loss of Secisbp2 reduced the abundance of many, but not all, selenoprotein mRNAs. Transcript-specific and gender-selective effects on selenoprotein mRNA abundance were greater in Secisbp2-deficient hepatocytes than in tRNA[Ser]Sec-deficient cells. Despite the massive reduction of Dio1 and Sepp1 mRNAs, significantly more corresponding protein was detected in primary hepatocytes lacking Secisbp2 than in cells lacking tRNA[Ser]Sec. Regarding selenoprotein expression, compensatory nuclear factor, erythroid-derived, like 2 (Nrf2)-dependent gene expression, or embryonic development, phenotypes were always milder in Secisbp2-deficient than in tRNA[Ser]Sec-deficient mice.
  
  
  METHODS
  We report the first Secisbp2 mutant mouse models. The conditional mutants provide a model for analyzing Secisbp2 function in organs not accessible in patients.
  
  
  CONCLUSIONS
  In hepatocyte-specific conditional mouse models, Secisbp2 gene inactivation is less detrimental than tRNA[Ser]Sec inactivation. A role of Secisbp2 in stabilizing selenoprotein mRNAs in vivo was uncovered.
authors.affiliation: 1 Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin , Berlin, Germany .
authors.forename: Sandra
authors.initials: S
authors.lastname: Seeher
authors.forename: Tarik
authors.initials: T
authors.lastname: Atassi
authors.forename: Yassin
authors.initials: Y
authors.lastname: Mahdi
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.forename: Doreen
authors.initials: D
authors.lastname: Braun
authors.forename: Eva K
authors.initials: EK
authors.lastname: Wirth
authors.forename: Marc O
authors.initials: MO
authors.lastname: Klein
authors.forename: Nathalie
authors.initials: N
authors.lastname: Reix
authors.forename: Angela C
authors.initials: AC
authors.lastname: Miniard
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
authors.forename: Donna M
authors.initials: DM
authors.lastname: Driscoll
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D023061:Gene Order; D020868:Gene Silencing; D018390:Gene Targeting; D056426:Genetic Loci; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D051140:Selenoproteins / Q000235:genetics*
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C577859:SECIS-binding protein 2, mouse; D051140:Selenoproteins