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Amhr2-Cre-Mediated Global Tspo Knockout.

Authors
  • Fan, Jinjiang1, 2
  • Campioli, Enrico1, 2
  • Sottas, Chantal3
  • Zirkin, Barry4
  • Papadopoulos, Vassilios1, 2, 3
  • 1 The Research Institute of the McGill University Health Centre.
  • 2 Department of Medicine, McGill University, Montreal, Quebec, Canada. , (Canada)
  • 3 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, US.
  • 4 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, US.
Type
Published Article
Journal
Journal of the Endocrine Society
Publisher
The Endocrine Society
Publication Date
Feb 01, 2020
Volume
4
Issue
2
Identifiers
DOI: 10.1210/jendso/bvaa001
PMID: 32099945
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Although the role of translocator protein (TSPO) in cholesterol transport in steroid-synthesizing cells has been studied extensively, recent studies of TSPO genetic depletion have questioned its role. Amhr2-Cre mice have been used to generate Leydig cell-specific Tspo conditional knockout (cKO) mice. Using the same Cre line, we were unable to generate Tspo cKO mice possibly because of genetic linkage between Tspo and Amhr2 and coexpression of Amhr2-Cre and Tspo in early embryonic development. We found that Amhr2-Cre is expressed during preimplantation stages, resulting in global heterozygous mice (gHE; Amhr2-Cre+/-,Tspo -/+). Two gHE mice were crossed, generating Amhr2-Cre-mediated Tspo global knockout (gKO; Tspo -/-) mice. We found that 33.3% of blastocysts at E3.5 to E4.5 showed normal morphology, whereas 66.7% showed delayed development, which correlates with the expected Mendelian proportions of Tspo +/+ (25%), Tspo -/- (25%), and Tspo +/- (50%) genotypes from crossing 2 Tspo -/+ mice. Adult Tspo gKO mice exhibited disturbances in neutral lipid homeostasis and reduced intratesticular and circulating testosterone levels, but no change in circulating basal corticosterone levels. RNA-sequencing data from mouse adrenal glands and lungs revealed transcriptome changes in response to the loss of TSPO, including changes in several cholesterol-binding and transfer proteins. This study demonstrates that Amhr2-Cre can be used to produce Tspo gKO mice instead of cKO, and can serve as a new global "Cre deleter." Moreover, our results show that Tspo deletion causes delayed preimplantation embryonic development, alters neutral lipid storage and steroidogenesis, and leads to transcriptome changes that may reflect compensatory mechanisms in response to the loss of function of TSPO. © Endocrine Society 2020.

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