title: Thyroid hormone limits postnatal Sertoli cell proliferation in vivo by activation of its alpha1 isoform receptor (TRalpha1) present in these cells and by regulation of Cdk4/JunD/c-myc mRNA levels in mice.
abstract: Hypo- and hyperthyroidism alter testicular functions in the young. Among T3 receptors, TRalpha1 is ubiquitous, and its previously described knockout leads to an increase in testis weight and sperm production. We tested, for the first time, the hypothesis that TRalpha1-dependent regulation of Sertoli cell (SC) proliferation was directly regulated by TRalpha1 present in these cells. Thus, after crossing with the AMH-Cre line, we generated and analyzed a new line that expressed a dominant-negative TRalpha1 isoform (TRalpha(AMI)) in SCs only. So-called TRalpha(AMI)-SC (TRalpha(AMI/+) Cre(+)) mice exhibited similar phenotypic features to the knockout line: heavier testicular weight and higher sperm reserve, in comparison with their adequate controls (TRalpha(AMI/+) Cre(-)). SC density increased significantly as a result of a higher proliferative index at ages Postnatal Day (P) 0 and P3. When explants of control testes were cultured (at age P3), a significant decrease in the proliferation of SCs was observed in response to an excess of T3. This response was not observed in the TRalpha(AMI)-SC and knockout lines. Finally, when TRalpha(AMI) is present in SCs, the phenotype observed is similar to that of the knockout line. This study demonstrates that T3 limits postnatal SC proliferation by activation of TRalpha1 present in these cells. Moreover, quantitative RT-PCR provided evidence that regulation of the Cdk4/JunD/c-myc pathway was involved in this negative control.
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France.
authors.forename: Betty
authors.initials: B
authors.lastname: Fumel
authors.forename: Marie-Justine
authors.initials: MJ
authors.lastname: Guerquin
authors.forename: Gabriel
authors.initials: G
authors.lastname: Livera
authors.forename: Christophe
authors.initials: C
authors.lastname: Staub
authors.forename: Michèle
authors.initials: M
authors.lastname: Magistrini
authors.forename: Christophe
authors.initials: C
authors.lastname: Gauthier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Flamant
authors.forename: Florian
authors.initials: F
authors.lastname: Guillou
authors.forename: Sophie
authors.initials: S
authors.lastname: Fouchécourt
mesh_terms: D000818:Animals; D001483:Base Sequence; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013737:Testis / Q000166:cytology / Q000254:growth & development; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C489428:Myc protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; C528955:junD protein, mouse; D014284:Triiodothyronine; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4