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Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling

Barthold, Julia S.; Robbins, Alan; Wang, Yanping; Pugarelli, Joan; Mateson, Abigail; Anand-Ivell, Ravinder; Ivell, Richard; McCahan, Suzanne M.; Akins, Robert E., Jr.

Authors

Julia S. Barthold

Alan Robbins

Yanping Wang

Joan Pugarelli

Abigail Mateson

Richard Ivell

Suzanne M. McCahan

Robert E., Jr. Akins



Abstract

Cryptorchidism, or undescended testis, is a common male genital anomaly of unclear etiology. Hormonal stimulation of the developing fetal gubernaculum by testicular androgens and insulin-like 3 (INSL3) is required for testicular descent. In studies of the orl fetal rat, one of several reported strains with inherited cryptorchidism, we studied hormone levels, gene expression in intact and hormone-stimulated gubernaculum, and imaging of the developing cremaster muscle facilitated by a tissue clearing protocol to further characterize development of the orl gubernaculum. Abnormal localization of the inverted gubernaculum was visible soon after birth. In the orl fetus, testicular testosterone, gubernacular androgen-responsive transcript levels, and muscle-specific gene expression were reduced. However, the in vitro transcriptional response of the orl gubernaculum to androgen was largely comparable to wild type (wt). In contrast, increases in serum INSL3, gubernacular INSL3-responsive transcript levels, expression of the INSL3 receptor, Rxfp2, and the response of the orl gubernaculum to INSL3 in vitro all suggest enhanced activation of INSL3/RXFP2 signaling in the orl rat. However, DNA sequence analysis did not identify functional variants in orl Insl3. Finally, combined analysis of the present and previous studies of the orl transcriptome confirmed altered expression of muscle and cellular motility genes, and whole mount imaging revealed aberrant muscle pattern formation in the orl fetal gubernaculum. The nature and prevalence of developmental muscle defects in the orl gubernaculum are consistent with the cryptorchid phenotype in this strain. These data suggest impaired androgen and enhanced INSL3 signaling in the orl fetus accompanied by defective cremaster muscle development.

Citation

Barthold, J. S., Robbins, A., Wang, Y., Pugarelli, J., Mateson, A., Anand-Ivell, R., …Akins, R. E. J. (2014). Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling. Biology of Reproduction, 91(2), https://doi.org/10.1095/biolreprod.114.119560

Journal Article Type Article
Acceptance Date Jun 10, 2014
Online Publication Date Jun 25, 2014
Publication Date Aug 1, 2014
Deposit Date Mar 22, 2017
Publicly Available Date Mar 22, 2017
Journal Biology of Reproduction
Print ISSN 0006-3363
Electronic ISSN 1529-7268
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 91
Issue 2
DOI https://doi.org/10.1095/biolreprod.114.119560
Keywords Androgen receptor, cryptorchidism, gubernaculum, insulin-like 3, male reproductive tract
Public URL http://eprints.nottingham.ac.uk/id/eprint/41429
Publisher URL https://academic.oup.com/biolreprod/article/2433948/Cryptorchidism
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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