Home LiteratureArticle Details
PMID: 22701646 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Dicer1 ablation in the mouse epididymis causes dedifferentiation of the epithelium and imbalance in sex steroid signaling.

PloS one ·Vol. 7 ·No. 6 ·2012-00-00 ·Pages e38457

Björkgren I, Saastamoinen L, Krutskikh A, Huhtaniemi I, Poutanen M, Sipilä P

Abstract

The postnatal development of the epididymis is a complex process that results in a highly differentiated epithelium, divided into several segments. Recent studies indicate a role for RNA interference (RNAi) in the development of the epididymis, however, the actual requirement for RNAi has remained elusive. Here, we present the first evidence of a direct need for RNAi in the differentiation of the epididymal epithelium. By utilizing the Cre-LoxP system we have generated a conditional knock-out of Dicer1 in the two most proximal segments of the mouse epididymis. Recombination of Dicer1, catalyzed by Defb41(iCre/wt), took place before puberty, starting from 12 days postpartum. Shortly thereafter, downregulation of the expression of two genes specific for the most proximal epididymis (lipocalin 8 and cystatin 8) was observed. Following this, segment development continued until week 5 at which age the epithelium started to regress back to an undifferentiated state. The dedifferentiated epithelium also showed an increase in estrogen receptor 1 expression while the expression of androgen receptor and its target genes; glutathione peroxidase 5, lipocalin 5 and cysteine-rich secretory protein 1 was downregulated, indicating imbalanced sex steroid signaling. At the time of the final epididymal development, Dicer1 acts as a regulator of signaling pathways essential for maintaining epithelial cell differentiation.

MeSH Terms
Animals Apoptosis/physiology Cell Dedifferentiation/physiology Cystatins/metabolism DEAD-box RNA Helicases/deficiency,genetics Epididymis/cytology,growth & development,metabolism Epithelial Cells/physiology Estrogen Receptor alpha/metabolism Gene Expression Regulation, Developmental/physiology Gene Knockout Techniques Gonadal Steroid Hormones/metabolism Histological Techniques Immunohistochemistry Lipocalins/metabolism Male Mice RNA Interference Receptors, Androgen/metabolism Ribonuclease III/deficiency,genetics Signal Transduction/genetics beta-Defensins/metabolism
Chemicals
Cystatins Estrogen Receptor alpha Gonadal Steroid Hormones Lcn8 protein, mouse Lipocalins Receptors, Androgen beta-Defensins Cst8 protein, mouse Dicer1 protein, mouse Ribonuclease III DEAD-box RNA Helicases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Björkgren Ida
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
Saastamoinen Lauri
Krutskikh Anton
Huhtaniemi Ilpo
Poutanen Matti
Sipilä Petra
References (59)
59 references, click to expand
  1. Localization of androgen and estrogen receptors in adult male mouse reproductive tract.
    J Androl. 2002 Nov-Dec;23(6):870-81 PMID: 12399534
  2. Comparative expression of laminin and smooth muscle actin in the testis and epididymis of poultry and rabbit.
    J Mol Histol. 2009 Oct;40(5-6):407-16 PMID: 20157768
  3. Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man.
    Hum Reprod Update. 2001 May-Jun;7(3):236-47 PMID: 11392370
  4. Essential roles of androgen signaling in Wolffian duct stabilization and epididymal cell differentiation.
    Endocrinology. 2011 Apr;152(4):1640-51 PMID: 21303954
  5. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb.
    Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10898-903 PMID: 16040801
  6. Structural differentiation of the epithelial cells of the testicular excurrent duct system of rats during postnatal development.
    Anat Rec. 1992 Jun;233(2):205-28 PMID: 1605386
  7. MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function.
    Gastroenterology. 2010 Nov;139(5):1654-64, 1664.e1 PMID: 20659473
  8. Morphologic changes in efferent ductules and epididymis in estrogen receptor-alpha knockout mice.
    J Androl. 2000 Jan-Feb;21(1):107-21 PMID: 10670526
  9. Multidirectional interplay between nuclear receptors and microRNAs.
    Curr Opin Pharmacol. 2010 Dec;10(6):637-42 PMID: 20829111
  10. The critical time window for androgen-dependent development of the Wolffian duct in the rat.
    Endocrinology. 2007 Jul;148(7):3185-95 PMID: 17431008
  11. Severe subfertility in mice with androgen receptor inactivation in sex accessory organs but not in testis.
    Endocrinology. 2008 Jul;149(7):3330-8 PMID: 18356274
  12. MicroRNA expression is required for pancreatic islet cell genesis in the mouse.
    Diabetes. 2007 Dec;56(12):2938-45 PMID: 17804764
  13. Residual microRNA expression dictates the extent of inner ear development in conditional Dicer knockout mice.
    Dev Biol. 2009 Apr 15;328(2):328-41 PMID: 19389351
  14. Gene expression in the epididymis.
    Int Rev Cytol. 1999;188:133-202 PMID: 10208012
  15. Role for a bidentate ribonuclease in the initiation step of RNA interference.
    Nature. 2001 Jan 18;409(6818):363-6 PMID: 11201747
  16. Testosterone-induced upregulation of miRNAs in the female mouse liver.
    Steroids. 2010 Dec;75(12):998-1004 PMID: 20600201
  17. Gene regulation by microRNAs.
    Curr Opin Genet Dev. 2006 Apr;16(2):203-8 PMID: 16503132
  18. Transcription and translation of estrogen receptor-beta in the male reproductive tract of estrogen receptor-alpha knock-out and wild-type mice.
    Endocrinology. 1998 Jun;139(6):2982-7 PMID: 9607809
  19. Suppression of androgen action and the induction of gross abnormalities of the reproductive tract in male rats treated neonatally with diethylstilbestrol.
    J Androl. 2001 Mar-Apr;22(2):323-38 PMID: 11229807
  20. Targeted inactivation of the androgen receptor gene in murine proximal epididymis causes epithelial hypotrophy and obstructive azoospermia.
    Endocrinology. 2011 Feb;152(2):689-96 PMID: 21084446
  21. Essential roles of inhibin beta A in mouse epididymal coiling.
    Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11322-7 PMID: 17592132
  22. Castration induces apoptosis in the mouse epididymis during postnatal development.
    Endocr J. 2002 Feb;49(1):75-84 PMID: 12008753
  23. Age-dependent expression of the cystatin-related epididymal spermatogenic (Cres) gene in mouse testis and epididymis.
    Asian J Androl. 2007 May;9(3):305-11 PMID: 17486270
  24. Epididymal dysfunction initiated by the expression of simian virus 40 T-antigen leads to angulated sperm flagella and infertility in transgenic mice.
    Mol Endocrinol. 2002 Nov;16(11):2603-17 PMID: 12403849
  25. Expression of androgen receptor mRNA during mouse embryogenesis.
    Mech Dev. 1998 Mar;72(1-2):175-8 PMID: 9533962
  26. Development of the caput epididymidis studied by expressed proteins (a glutamate transporter, a lipocalin and beta-galactosidase) in the c-ros knockout and wild-type mice with prepubertally ligated efferent ducts.
    Cell Tissue Res. 2004 Jul;317(1):23-34 PMID: 15185139
  27. Biological functions of microRNAs: a review.
    J Physiol Biochem. 2011 Mar;67(1):129-39 PMID: 20981514
  28. Fluid and electrolyte reabsorption in the ductuli efferentes testis.
    J Reprod Fertil Suppl. 1998;53:1-14 PMID: 10645261
  29. Development of cell types and of regional differences in the postnatal rat epididymis.
    Am J Anat. 1979 Jan;154(1):27-55 PMID: 760488
  30. Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues.
    J Intern Med. 2008 Aug;264(2):128-42 PMID: 18513343
  31. Infertile spermatozoa of c-ros tyrosine kinase receptor knockout mice show flagellar angulation and maturational defects in cell volume regulatory mechanisms.
    Biol Reprod. 1999 Oct;61(4):1062-9 PMID: 10491645
  32. Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function.
    Biol Reprod. 2010 May;82(5):948-57 PMID: 20130267
  33. Epididymal hypo-osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse.
    Biol Reprod. 2010 May;82(5):958-67 PMID: 20130266
  34. Aberrant T cell differentiation in the absence of Dicer.
    J Exp Med. 2005 Jul 18;202(2):261-9 PMID: 16009718
  35. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells.
    Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19983-8 PMID: 18056640
  36. Defective postnatal development of the male reproductive tract in LGR4 knockout mice.
    Dev Biol. 2006 Feb 15;290(2):421-34 PMID: 16406039
  37. miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth.
    Cancer Res. 2009 Sep 15;69(18):7165-9 PMID: 19738047
  38. Cellular signaling by fibroblast growth factors (FGFs) and their receptors (FGFRs) in male reproduction.
    Endocr Rev. 2008 Apr;29(2):193-216 PMID: 18216218
  39. Gene duplication gives rise to a new 17-kilodalton lipocalin that shows epididymal region-specific expression and testicular factor(s) regulation.
    Endocrinology. 2001 Mar;142(3):1296-308 PMID: 11181548
  40. Comparative profiling of genes and miRNAs expressed in the newborn, young adult, and aged human epididymides.
    Acta Biochim Biophys Sin (Shanghai). 2010 Feb;42(2):145-53 PMID: 20119626
  41. Development and morphogenesis of the Wolffian/epididymal duct, more twists and turns.
    Dev Biol. 2009 Jan 1;325(1):6-14 PMID: 18992735
  42. Gene silencing in mammals by small interfering RNAs.
    Nat Rev Genet. 2002 Oct;3(10):737-47 PMID: 12360232
  43. Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1.
    J Cell Biol. 2001 Jan 22;152(2):325-34 PMID: 11266449
  44. miR-335 is involved in the rat epididymal development by targeting the mRNA of RASA1.
    Biochem Biophys Res Commun. 2010 Nov 12;402(2):222-7 PMID: 20933506
  45. MicroRNAs are mediators of androgen action in prostate and muscle.
    PLoS One. 2010 Oct 27;5(10):e13637 PMID: 21048966
  46. Androgen receptor expression in the caput epididymal epithelium is essential for development of the initial segment and epididymal spermatozoa transit.
    Endocrinology. 2011 Feb;152(2):718-29 PMID: 21177831
  47. New insights into epididymal biology and function.
    Hum Reprod Update. 2009 Mar-Apr;15(2):213-27 PMID: 19136456
  48. Regulation of gamma-glutamyl transpeptidase catalytic activity and protein level in the initial segment of the rat epididymis by testicular factors: role of basic fibroblast growth factor.
    Biol Reprod. 1998 Jan;58(1):197-206 PMID: 9472941
  49. Dicer is required for proper liver zonation.
    J Pathol. 2009 Nov;219(3):365-72 PMID: 19718708
  50. Characterization of fibroblast growth factor receptors expressed in principal cells in the initial segment of the rat epididymis.
    Biol Reprod. 2003 Jun;68(6):2314-21 PMID: 12606343
  51. Dicer is essential for mouse development.
    Nat Genet. 2003 Nov;35(3):215-7 PMID: 14528307
  52. Establishment of cell-cell cross talk in the epididymis: control of luminal acidification.
    J Androl. 2011 Nov-Dec;32(6):576-86 PMID: 21441423
  53. Sources of oestrogen in the testis and reproductive tract of the male.
    Int J Androl. 1999 Aug;22(4):211-23 PMID: 10442293
  54. The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines.
    Mol Endocrinol. 2007 May;21(5):1132-47 PMID: 17312270
  55. Expression of functional aromatase in the epididymis: role of androgens and LH in modulation of expression and activity.
    Mol Cell Endocrinol. 2006 Apr 25;249(1-2):40-50 PMID: 16569475
  56. Estrogens regulate humans and rabbit epididymal contractility through the RhoA/Rho-kinase pathway.
    J Sex Med. 2009 Aug;6(8):2173-86 PMID: 19453906
  57. Immunohistochemical studies of the epididymal duct in Egyptian water buffalo (Bubalus bubalis).
    Acta Histochem. 2011 Feb;113(2):96-102 PMID: 19836061
  58. LGR4 regulates the postnatal development and integrity of male reproductive tracts in mice.
    Biol Reprod. 2007 Feb;76(2):303-13 PMID: 17079737
  59. The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis.
    Genes Dev. 1996 May 15;10(10):1184-93 PMID: 8675006
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0038457
Published
2012-00-00
Epub
2012-00-06
Pages
e38457
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3368854
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0038457 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2