scholarly journals Smooth Muscle Cell-Specific Knockout of Androgen Receptor: A New Model for Prostatic Disease

Endocrinology ◽  
2011 ◽  
Vol 152 (9) ◽  
pp. 3541-3551 ◽  
Author(s):  
Michelle Welsh ◽  
Lindsey Moffat ◽  
Alan McNeilly ◽  
David Brownstein ◽  
Philippa T. K. Saunders ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Androgen Receptor ◽  
Adult Mouse ◽  
Normal Prostate ◽  
Prostate Development ◽  
Prostate Weight ◽  
Androgen Action ◽  
Prostatic Diseases ◽  
And Function ◽  
Insight Into

Androgen-driven stromal-epithelial interactions play a key role in normal prostate development and function as well as in the progression of common prostatic diseases such as benign prostatic hyperplasia and prostate cancer. However, exactly how, and via which cell type, androgens mediate their effects in the adult prostate remains unclear. This study investigated the role for smooth muscle (SM) androgen signaling in normal adult prostate homeostasis and function using mice in which androgen receptor was selectively ablated from prostatic SM cells. In adulthood the knockout (KO) mice displayed a 44% reduction in prostate weight and exhibited histological abnormalities such as hyperplasia, inflammation, fibrosis, and reduced expression of epithelial, SM, and stem cell identify markers (e.g. p63 reduced by 27% and Pten by 31%). These changes emerged beyond puberty and were not explained by changes in serum hormones. Furthermore, in response to exogenous estradiol, adult KO mice displayed an 8.5-fold greater increase in prostate weight than controls and developed urinary retention. KO mice also demonstrated a reduced response to castration compared with controls. Together these results demonstrate that prostate SM cells are vital in mediating androgen-driven stromal-epithelial interactions in adult mouse prostates, determining cell identity and function and limiting hormone-dependent epithelial cell proliferation. This novel mouse model provides new insight into the possible role for SM androgen action in prostate disease.

scholarly journals Epithelial Phenotypes in the Developing Human Prostate

2007 ◽  
Vol 55 (9) ◽  
pp. 885-890 ◽  
Author(s):  
Guy Letellier ◽  
Marie-José Perez ◽  
Mokrane Yacoub ◽  
Pierre Levillain ◽  
Olivier Cussenot ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Growth Factor ◽  
Regulatory Function ◽  
Basal Cells ◽  
Normal Prostate ◽  
Prostate Development ◽  
Proliferation And Apoptosis ◽  
Normal Prostate Tissue ◽  
Epidermal Growth ◽  
Luminal Cells

An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.

scholarly journals Androgen receptor knockout and knock-in mouse models

2008 ◽  
Vol 42 (1) ◽  
pp. 11-17 ◽  
Author(s):  
S Kerkhofs ◽  
S Denayer ◽  
A Haelens ◽  
F Claessens
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Steroid Hormones ◽  
Mouse Models ◽  
Reproductive Development ◽  
Androgen Insensitivity Syndrome ◽  
Androgen Insensitivity ◽  
And Function ◽  
Insight Into ◽  
Working Mechanisms

Androgens play an important role in male reproductive development and function. These steroid hormones mediate their actions by binding to the androgen receptor (AR). Diseases such as androgen insensitivity syndrome, prostate cancer, Kennedy's disease, and infertility can be caused by mutations in the AR. To get a better insight into the molecular working mechanisms of the AR, several knockout and knock-in mouse models have been developed. These models are reviewed here and are compared with human diseases.

scholarly journals Development and Function of the Adult Generation of Leydig Cells in Mice with Sertoli Cell-Selective or Total Ablation of the Androgen Receptor

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 4117-4126 ◽  
Author(s):  
Karel De Gendt ◽  
Nina Atanassova ◽  
Karen A. L. Tan ◽  
Luiz Renato de França ◽  
Gleydes Gambogi Parreira ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Growth Factor ◽  
Sertoli Cell ◽  
Leydig Cells ◽  
Platelet Derived Growth Factor ◽  
Testosterone Levels ◽  
Androgen Action ◽  
Serum Lh ◽  
D 12 ◽  
And Function

Abstract It is established that androgens and unidentified Sertoli cell (SC)-derived factors can influence the development of adult Leydig cells (LC) in rodents, but the mechanisms are unclear. We evaluated adult LC development and function in SC-selective androgen receptor (AR) knockout (SCARKO) and complete AR knockout (ARKO) mice. In controls, LC number increased 26-fold and LC size increased by approximately 2-fold between 12 and 140 d of age. LC number in SCARKOs was normal on d 12, but was reduced by more than 40% at later ages, although LC were larger and contained more lipid droplets and mitochondria than control LC by adulthood. ARKO LC number was reduced by up to 83% at all ages compared with controls, and LC size did not increase beyond d 12. Serum LH and testosterone levels and seminal vesicle weights were comparable in adult SCARKOs and controls, whereas LH levels were elevated 8-fold in ARKOs, although testosterone levels appeared normal. Immunohistochemistry and quantitative PCR for LC-specific markers indicated steroidogenic function per LC was probably increased in SCARKOs and reduced in ARKOs. In SCARKOs, insulin-like factor-3 and estrogen sulfotransferase (EST) mRNA expression were unchanged and increased 3-fold, respectively, compared with controls, whereas the expression of both was reduced more than 90% in ARKOs. Changes in EST expression, coupled with reduced platelet-derived growth factor-A expression, are potential causes of altered LC number and function in SCARKOs. These results show that loss of androgen action on SC has major consequences for LC development, and this could be mediated indirectly via platelet-derived growth factor-A and/or estrogens/EST.

scholarly journals Influence of stromal–epithelial interactions on androgen action

2014 ◽  
Vol 21 (4) ◽  
pp. T147-T160 ◽  
Author(s):  
Cera M Nieto ◽  
Leah C Rider ◽  
Scott D Cramer
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Normal Development ◽  
Differentially Expressed ◽  
Androgen Action ◽  
Autocrine Control ◽  
And Function ◽  
Mammary Tissues

Androgen receptor (AR) signaling is vital to the development and function of the prostate and is a key pathway in prostate cancer. AR is differentially expressed in the stroma and epithelium, with both paracrine and autocrine control throughout the prostate. Stromal–epithelial interactions within the prostate are commonly dependent on AR signaling and expression. Alterations in these pathways can promote tumorigenesis. AR is also expressed in normal and malignant mammary tissues. Emerging data indicate a role for AR in certain subtypes of breast cancer that has the potential to be exploited therapeutically. The aim of this review is to highlight the importance of these interactions in normal development and tumorigenesis, with a focus on the prostate and breast.

Prenatal exposure to testosterone masculinises the female gerbil and promotes the development of lesions in the prostate (Skene’s gland)

2015 ◽  
Vol 27 (7) ◽  
pp. 1000 ◽  
Author(s):  
Manoel F. Biancardi ◽  
Ana P. S. Perez ◽  
Cássia Regina Suzuki Caires ◽  
Rejane M. Góes ◽  
Patrícia S. L. Vilamaior ◽  
...  
Keyword(s):  
Prenatal Exposure ◽  
Vaginal Wall ◽  
Experimental Models ◽  
Prostatic Tissue ◽  
Postnatal Life ◽  
Normal Prostate ◽  
Anogenital Distance ◽  
Morphological Alterations ◽  
Prostate Development ◽  
Prostatic Diseases

Androgenic imbalance may disrupt prostate development, leading to morphological alterations in adulthood and predisposing this gland to develop diseases during ageing. However, little is known about the endocrine disruption of the prostate that is caused by androgenic compounds, especially in female experimental models. Therefore, this study aimed to evaluate the prostates of aged female gerbils exposed to testosterone at certain periods in intrauterine and postnatal life, to determine whether exposure at a particular age increases susceptibility to prostatic lesions in these animals. To this end, morphological, stereological, immunohistochemical and immunofluorescence analyses were employed. It was found that females exposed to testosterone during intrauterine life were masculinised, showing increased anogenital distance, absence of the vaginal opening and ectopic development of prostatic tissue. Several areas of adenomatous hyperplasia, generally associated with inflammatory foci and mainly located in the ectopic prostatic tissue around the vaginal wall, were also observed. In conclusion, the results showed that abnormal prenatal exposure to testosterone severely affects the reproductive systems of female animals by disrupting normal prostate morphogenesis and increasing susceptibility to the development of prostatic diseases during ageing.

scholarly journals Deletion of Androgen Receptor in the Smooth Muscle of the Seminal Vesicles Impairs Secretory Function and Alters Its Responsiveness to Exogenous Testosterone and Estradiol

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3374-3385 ◽  
Author(s):  
Michelle Welsh ◽  
Lindsey Moffat ◽  
Laura Jack ◽  
Alan McNeilly ◽  
David Brownstein ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Epithelial Cell ◽  
Smooth Muscle Cells ◽  
Proliferative Response ◽  
Androgen Receptors ◽  
Muscle Cells ◽  
Structure And Function ◽  
Seminal Vesicles ◽  
Androgen Action ◽  
And Function

The seminal vesicles (SVs), like much of the male reproductive tract, depend on androgen-driven stromal-epithelial interactions for normal development, structure, and function. The primary function of the SVs is to synthesize proteins that contribute to the seminal plasma and this is androgen dependent. However, the cell-specific role for androgen action in adult SVs remains unclear. This study analyzed the SV in mice with targeted ablation of androgen receptors specifically in smooth muscle cells (PTM-ARKO) to determine in vivo whether it is androgen action in a subset of the SV stroma, the smooth muscle cells, that drives epithelial function and identity. These mice have significantly smaller SVs in adulthood with less smooth muscle and reduced epithelial cell height. Less epithelial cell proliferation was observed in adult PTM-ARKO SVs, compared with controls, and production of seminal proteins was reduced, indicating global impairment of epithelial cell function in PTM-ARKO SVs. None of these changes could be explained by altered serum testosterone or estradiol concentrations. We also demonstrate altered SV responsiveness to exogenous testosterone and estradiol in PTM-ARKO mice, indicating that smooth muscle androgen receptors may limit the SV epithelial proliferative response to exogenous estrogens. These results therefore demonstrate that the smooth muscle cells play a vital role in androgen-driven stromal-epithelial interactions in the SV, determining epithelial cell structure and function as well as limiting the SV epithelial proliferative response to exogenous estrogens.

Chaperones for proper androgen action – a plethora of assistance to androgen receptor function

2012 ◽  
Vol 11 (1) ◽  
Author(s):  
Wiebke Hessenkemper ◽  
Aria Baniahmad
Keyword(s):  
Androgen Receptor ◽  
Molecular Chaperones ◽  
Glucocorticoid Receptors ◽  
Intracellular Localization ◽  
Progesterone Receptors ◽  
Normal Prostate ◽  
Androgen Action ◽  
Age Related ◽  
Shock Proteins ◽  
Prostate Growth

AbstractThe androgen receptor (AR) plays a major role for normal prostate growth and also promotes the development and progression of prostate cancer (PCa). PCa, an important age-related disease, is one of the most commonly diagnosed cancers and the second leading cause of cancer mortality for men in Western countries. AR function and activity are regulated by molecular chaperones. The AR belongs to the steroid hormone receptor (SHR) family and can be activated by androgens such as dihydrotestosterone. SHRs are ligand-dependent transcription factors that are predominantly localized in the cytoplasm in the absence of their appropriate ligand. Upon hormone binding, translocation to the nucleus occurs as shown for glucocorticoid receptors, mineralocorticoid receptors, or the AR, while others, such as estrogen and progesterone receptors, are mainly nuclear. Importantly, the newly synthesized and unliganded receptors bind stepwise with chaperones then being associated in a dynamic chaperone heterocomplex, including heat shock proteins. It emerges that chaperones are very important, not only in the proper folding of the AR but they are also involved in receptor stability, intracellular localization and androgen-controlled transcription. Accordingly, chaperones may be interesting future targets for PCa treatment. In this review we will summarize the involvement of chaperones controlling AR activity.

Structure and function of neural networks in the retina

1988 ◽  
Vol 46 ◽  
pp. 26-27
Author(s):  
Peter Sterling
Keyword(s):  
Ganglion Cells ◽  
Three Dimensional ◽  
Structure And Function ◽  
Synaptic Connections ◽  
Visual Axis ◽  
One Dimensional ◽  
Cat Retina ◽  
Ultrathin Sections ◽  
And Function ◽  
Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

Computational Approaches to Predict the Non-canonical DNAs

2019 ◽  
Vol 14 (6) ◽  
pp. 470-479 ◽  
Author(s):  
Nazia Parveen ◽  
Amen Shamim ◽  
Seunghee Cho ◽  
Kyeong Kyu Kim
Keyword(s):  
Computational Methods ◽  
Genetic Instability ◽  
Computational Prediction ◽  
Structure And Function ◽  
Sequence Motifs ◽  
Computational Approaches ◽  
Functional Roles ◽  
And Function ◽  
Genetic Events ◽  
Insight Into

Background: Although most nucleotides in the genome form canonical double-stranded B-DNA, many repeated sequences transiently present as non-canonical conformations (non-B DNA) such as triplexes, quadruplexes, Z-DNA, cruciforms, and slipped/hairpins. Those noncanonical DNAs (ncDNAs) are not only associated with many genetic events such as replication, transcription, and recombination, but are also related to the genetic instability that results in the predisposition to disease. Due to the crucial roles of ncDNAs in cellular and genetic functions, various computational methods have been implemented to predict sequence motifs that generate ncDNA. Objective: Here, we review strategies for the identification of ncDNA motifs across the whole genome, which is necessary for further understanding and investigation of the structure and function of ncDNAs. Conclusion: There is a great demand for computational prediction of non-canonical DNAs that play key functional roles in gene expression and genome biology. In this study, we review the currently available computational methods for predicting the non-canonical DNAs in the genome. Current studies not only provide an insight into the computational methods for predicting the secondary structures of DNA but also increase our understanding of the roles of non-canonical DNA in the genome.

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