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Restoration of spermatogenesis and male fertility using an androgen receptor transgene

Walker, WH and Easton, E and Moreci, RS and Toocheck, C and Anamthathmakula, P and Jeyasuria, P (2015) Restoration of spermatogenesis and male fertility using an androgen receptor transgene. PLoS ONE, 10 (3).

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Abstract

Androgens signal through the androgen receptor (AR) to regulate male secondary sexual characteristics, reproductive tract development, prostate function, sperm production, bone and muscle mass as well as body hair growth among other functions. We developed a transgenic mouse model in which endogenous AR expression was replaced by a functionally modified AR transgene. A bacterial artificial chromosome (BAC) was constructed containing all AR exons and introns plus 40 kb each of 5' and 3' regulatory sequence. Insertion of an internal ribosome entry site and the EGFP gene 3' to AR allowed co-expression of AR and EGFP. Pronuclear injection of the BAC resulted in six founder mice that displayed EGFP production in appropriate AR expressing tissues. The six founder mice were mated into a Sertoli cell specific AR knockout (SCARKO) background in which spermatogenesis is blocked at the meiosis stage of germ cell development. The AR-EGFP transgene was expressed in a cyclical manner similar to that of endogenous AR in Sertoli cells and fertility was restored as offspring were produced in the absence of Sertoli cell AR. Thus, the AREGFP transgene under the control of AR regulatory elements is capable of rescuing AR function in a cell selective, AR-null background. These initial studies provide proof of principle that a strategy employing the AR-EGFP transgene can be used to understand AR functions. Transgenic mice expressing selective modifications of the AR-EGFP transgene may provide crucial information needed to elicit the molecular mechanisms by which AR acts in the testis and other androgen responsive tissues.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Walker, WHwalkerw@pitt.eduWALKERW
Easton, E
Moreci, RS
Toocheck, C
Anamthathmakula, P
Jeyasuria, P
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSchlatt, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > McGowan Institute for Regenerative Medicine
Date: 24 March 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0120783
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
Date Deposited: 23 Aug 2016 13:56
Last Modified: 31 Mar 2021 21:55
URI: http://d-scholarship.pitt.edu/id/eprint/28498

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