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

Björkgren I, Saastamoinen L, Krutskikh A, Huhtaniemi I, Poutanen M, Sipilä P - PLoS ONE (2012)

Bottom Line: The postnatal development of the epididymis is a complex process that results in a highly differentiated epithelium, divided into several segments.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: At the time of the final epididymal development, Dicer1 acts as a regulator of signaling pathways essential for maintaining epithelial cell differentiation.

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Expression of Sex steroid receptors.(A) Immunostaining of two-month-old control mouse initial segment (IS) shows expression of Estrogen receptor 1 (ESR1) only in the narrow cells (indicated by arrows) while (B) the Dicer1fl/fl; Defb41iCre/wt mouse has ESR1 expression in most cells of the epithelium. (C, D) Staining for Androgen receptor. (D) Androgen receptor expression varied between Dicer1fl/fl; Defb41iCre/wt mice epididymides. Some samples had similar expression levels as the control while others showed areas of more weakly stained tissue. CAP, caput. Scale bars 100 µm. (E) Expression of androgen receptor (Ar) and estrogen receptor 1 and 2 (Esr1 and Esr2) as well as (F) AR target gene: glutathione peroxidase 5 (Gpx5), lipocalin 5 (Lcn5), cysteine-rich secretory protein 1 (Crisp1) mRNA in IS and CAP of 2 month-old control and Dicer1 conditional knock-out (cKO) mice epididymides. Expression values relative to L19 expression. Statistical significance was calculated from the expression levels of 3 control and 4 Dicer1fl/fl; Defb41iCre/wt mouse samples using the unpaired t-test. Statistical significance of changes is indicated as follows: ns, not significant; *, P≤0.05; ***, P≤0.001.
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pone-0038457-g006: Expression of Sex steroid receptors.(A) Immunostaining of two-month-old control mouse initial segment (IS) shows expression of Estrogen receptor 1 (ESR1) only in the narrow cells (indicated by arrows) while (B) the Dicer1fl/fl; Defb41iCre/wt mouse has ESR1 expression in most cells of the epithelium. (C, D) Staining for Androgen receptor. (D) Androgen receptor expression varied between Dicer1fl/fl; Defb41iCre/wt mice epididymides. Some samples had similar expression levels as the control while others showed areas of more weakly stained tissue. CAP, caput. Scale bars 100 µm. (E) Expression of androgen receptor (Ar) and estrogen receptor 1 and 2 (Esr1 and Esr2) as well as (F) AR target gene: glutathione peroxidase 5 (Gpx5), lipocalin 5 (Lcn5), cysteine-rich secretory protein 1 (Crisp1) mRNA in IS and CAP of 2 month-old control and Dicer1 conditional knock-out (cKO) mice epididymides. Expression values relative to L19 expression. Statistical significance was calculated from the expression levels of 3 control and 4 Dicer1fl/fl; Defb41iCre/wt mouse samples using the unpaired t-test. Statistical significance of changes is indicated as follows: ns, not significant; *, P≤0.05; ***, P≤0.001.


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

Björkgren I, Saastamoinen L, Krutskikh A, Huhtaniemi I, Poutanen M, Sipilä P - PLoS ONE (2012)

Expression of Sex steroid receptors.(A) Immunostaining of two-month-old control mouse initial segment (IS) shows expression of Estrogen receptor 1 (ESR1) only in the narrow cells (indicated by arrows) while (B) the Dicer1fl/fl; Defb41iCre/wt mouse has ESR1 expression in most cells of the epithelium. (C, D) Staining for Androgen receptor. (D) Androgen receptor expression varied between Dicer1fl/fl; Defb41iCre/wt mice epididymides. Some samples had similar expression levels as the control while others showed areas of more weakly stained tissue. CAP, caput. Scale bars 100 µm. (E) Expression of androgen receptor (Ar) and estrogen receptor 1 and 2 (Esr1 and Esr2) as well as (F) AR target gene: glutathione peroxidase 5 (Gpx5), lipocalin 5 (Lcn5), cysteine-rich secretory protein 1 (Crisp1) mRNA in IS and CAP of 2 month-old control and Dicer1 conditional knock-out (cKO) mice epididymides. Expression values relative to L19 expression. Statistical significance was calculated from the expression levels of 3 control and 4 Dicer1fl/fl; Defb41iCre/wt mouse samples using the unpaired t-test. Statistical significance of changes is indicated as follows: ns, not significant; *, P≤0.05; ***, P≤0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368854&req=5

pone-0038457-g006: Expression of Sex steroid receptors.(A) Immunostaining of two-month-old control mouse initial segment (IS) shows expression of Estrogen receptor 1 (ESR1) only in the narrow cells (indicated by arrows) while (B) the Dicer1fl/fl; Defb41iCre/wt mouse has ESR1 expression in most cells of the epithelium. (C, D) Staining for Androgen receptor. (D) Androgen receptor expression varied between Dicer1fl/fl; Defb41iCre/wt mice epididymides. Some samples had similar expression levels as the control while others showed areas of more weakly stained tissue. CAP, caput. Scale bars 100 µm. (E) Expression of androgen receptor (Ar) and estrogen receptor 1 and 2 (Esr1 and Esr2) as well as (F) AR target gene: glutathione peroxidase 5 (Gpx5), lipocalin 5 (Lcn5), cysteine-rich secretory protein 1 (Crisp1) mRNA in IS and CAP of 2 month-old control and Dicer1 conditional knock-out (cKO) mice epididymides. Expression values relative to L19 expression. Statistical significance was calculated from the expression levels of 3 control and 4 Dicer1fl/fl; Defb41iCre/wt mouse samples using the unpaired t-test. Statistical significance of changes is indicated as follows: ns, not significant; *, P≤0.05; ***, P≤0.001.
Bottom Line: The postnatal development of the epididymis is a complex process that results in a highly differentiated epithelium, divided into several segments.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: At the time of the final epididymal development, Dicer1 acts as a regulator of signaling pathways essential for maintaining epithelial cell differentiation.

Show MeSH
Related in: MedlinePlus