Abstract
BackgroundIn 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.MethodsThe 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.FindingsWe 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/SignificanceWe 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.
Highlights
Thyroid hormones, mainly represented by triiodothyronine (T3), and their nuclear receptors play important roles in the development, differentiation and function of various organs, including the male reproductive system [1,2]
Following our functional study in TRαAMI-Sertoli cells (SC) mice [8], we aimed to investigate the role of the TRα1 receptor in the regulation of steroidogenic activity using a novel functional Cre transgenic mouse, the aromatase-improved Cre recombinase (iCre) (ARO-iCre), that we generated in our laboratory and characterized for this study
To characterize the ARO-iCre transgenic line at cellular level, we crossed it to mice containing the ROSA26 Cre reporter (R26R) allele [31]. β-galactosidase (β-gal) activity resulting from loxP recombination at the R26R locus by ARO-iCre recombinase was observed at the periphery of the seminiferous tubules in SC and in the interstitium containing Leydig cells (LC) (Fig. 1C)
Summary
Mainly represented by triiodothyronine (T3), and their nuclear receptors play important roles in the development, differentiation and function of various organs, including the male reproductive system [1,2]. The effect of T3 on LC has been mostly investigated in rat species, using in vitro and in vivo pharmacological studies. In vivo, exogenous T3 in neonate rats leads to an increase in differentiated LC numbers and influences their proliferation [14]. Studies on neonatal hypothyroid rats showed a decrease in blood testosterone levels at adulthood [18,19]. As the modification was restricted to SC in TRαAMI-SC mice and ubiquitously present in TRαNull/Null mice, these two transgenic lines were not well suited to investigate direct T3 regulation of steroidogenesis by this receptor. Thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. The role of T3 in the regulation of steroidogenesis is still controversial.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
