Expression of dominant-negative thyroid hormone receptor alpha1 in Leydig and Sertoli cells demonstrates no additional defect compared with expression in Sertoli cells only

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. The TRαAMI knock-in allele allows the generation of transgenic mice expressing a dominan...

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Bibliographic Details
Published in:PloS one 2015-03, Vol.10 (3), p.e0119392-e0119392
Main Authors: Fumel, Betty, Froment, Pascal, Holzenberger, Martin, Livera, Gabriel, Monget, Philippe, Fouchécourt, Sophie
Format: Article
Language:English
Subjects:
Alleles
Analysis
Animals
Aromatase
Cell growth
Cell Proliferation
Cre recombinase
Cytochrome P-450
Endocrinology
Fertility
Gametes
Gene Expression
Gene mutation
Gene Targeting
Genetic engineering
Germ cells
Gonads
Hormones
Humans
Hypothyroidism
Laboratory animals
Leydig cells
Leydig Cells - metabolism
Life Sciences
Luteinizing hormone
Luteinizing Hormone - blood
Male
Males
Mice
Mice, Transgenic
mRNA
Other
Phenotype
Phenotypes
Pituitary hormones
Recombinase
Recombination
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Sertoli cells
Sertoli Cells - metabolism
Spermatozoa - metabolism
Steroidogenesis
Studies
Testis - metabolism
Testosterone
Testosterone - blood
Thyroid
Thyroid gland
Thyroid Hormone Receptors alpha - genetics
Transgenic mice
Triiodothyronine
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Summary: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. 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. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0119392