title: Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis.
abstract: Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate-limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR) and the translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcΔ/Δ) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase type I, and TSPO2 in TSPOcΔ/Δ testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis.
authors.affiliation: Department of Animal Science, College of Agriculture and Life Sciences (K.M., S.H.P., W.R.B., V.S.), Cornell University, Ithaca, New York 14853; and Department of Biochemistry and Molecular Medicine, School of Medicine (D.J.D., W.D.), University of California at Davis, Sacramento, California 95618.
authors.forename: Kanako
authors.initials: K
authors.lastname: Morohaku
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Pelton
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Daugherty
authors.forename: W Ronald
authors.initials: WR
authors.lastname: Butler
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
authors.forename: Vimal
authors.initials: V
authors.lastname: Selvaraj
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006728:Hormones / Q000096:biosynthesis*; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D018079:Receptors, GABA / Q000235:genetics* / Q000502:physiology; D013256:Steroids / Q000096:biosynthesis*; D013737:Testis / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood
chemical_list: C463819:Bzrp protein, mouse; D006728:Hormones; D018079:Receptors, GABA; D013256:Steroids; D013739:Testosterone