title: Expression of dominant-negative thyroid hormone receptor alpha1 in Leydig and Sertoli cells demonstrates no additional defect compared with expression in Sertoli cells only.
abstract: BACKGROUND
  In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial.
  
  
  METHODS
  The TRαAMI knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRα1 (thyroid receptor α1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO-iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter.
  
  
  RESULTS
  We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRαAMI specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRαAMI-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRαAMI-ARO males showed normal fertility. This phenotype is similar to TRαAMI-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRαAMI-ARO.
  
  
  CONCLUSIONS
  We concluded that the presence of a mutant TRαAMI allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRα1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis.
authors: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; CNRS, UMR7247 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; Université François Rabelais de Tours, F-37041, Tours, France; IFCE, F-37380, Nouzilly, France.
authors: Betty
authors: B
authors: Fumel
authors: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; CNRS, UMR7247 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; Université François Rabelais de Tours, F-37041, Tours, France; IFCE, F-37380, Nouzilly, France.
authors: Pascal
authors: P
authors: Froment
authors: INSERM and Sorbonne Universités-UPMC, UMRS 938, Hôpital Saint-Antoine, 75012, Paris, France.
authors: Martin
authors: M
authors: Holzenberger
authors: Laboratoire de Développement des Gonades, INSERM U967, CEA/DSV/iRCM/SCSR/LDG, Univ Paris Diderot, Sorbonne Paris Cité, Univ Paris Sud, F-92265, Fontenay-Aux-Roses, France.
authors: Gabriel
authors: G
authors: Livera
authors: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; CNRS, UMR7247 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; Université François Rabelais de Tours, F-37041, Tours, France; IFCE, F-37380, Nouzilly, France.
authors: Philippe
authors: P
authors: Monget
authors: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; CNRS, UMR7247 Physiologie de la Reproduction et des Comportements, F-37380, Nouzilly, France; Université François Rabelais de Tours, F-37041, Tours, France; IFCE, F-37380, Nouzilly, France.
authors: Sophie
authors: S
authors: Fouchécourt
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005298:Fertility; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D007985:Leydig Cells / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism*; D013094:Spermatozoa / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D013739:Testosterone; D007986:Luteinizing Hormone