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Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate.

Gamat M, Malinowski RL, Parkhurst LJ, Steinke LM, Marker PC - PLoS ONE (2015)

Bottom Line: Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens.DFMO also significantly decreased the expression of developmental regulatory gene Notch1.Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, United States of America.

ABSTRACT
The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

No MeSH data available.


Related in: MedlinePlus

Markers of prostatic budding in cultured UGS tissues.E16 UGS tissues were cultured in the control media, testosterone supplemented media or media with T+DFMO. Testosterone induced the expression of Nkx3.1 (A), Sox9 (B), Wif1 (C), Notch1 (H) and Srd5a2 (J). It did not induce the expression of Foxa1 (D), Shh (E), Ptc (F), Bmp4 (G) or Bmp7 (I). Culturing the UGS in T+DFMO significantly decreased expression of Nkx3.1 (A) and Notch1 (H). * p<0.05.
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pone.0139522.g007: Markers of prostatic budding in cultured UGS tissues.E16 UGS tissues were cultured in the control media, testosterone supplemented media or media with T+DFMO. Testosterone induced the expression of Nkx3.1 (A), Sox9 (B), Wif1 (C), Notch1 (H) and Srd5a2 (J). It did not induce the expression of Foxa1 (D), Shh (E), Ptc (F), Bmp4 (G) or Bmp7 (I). Culturing the UGS in T+DFMO significantly decreased expression of Nkx3.1 (A) and Notch1 (H). * p<0.05.

Mentions: Prostatic bud initial outgrowth is induced by androgens and coincides with up-regulation of genes. Inhibiting ornithine decarboxylase activity clearly affected prostatic bud formation, so we examined some of the pathways involved in prostatic bud initiation. Testosterone treatment significantly induced the expression of Nkx3.1 (Fig 7A), Sox9 (Fig 7B), Wif1 (Fig 7C), Notch1 (Fig 7G) and Srd5a2 (Fig 7I), which have previously been shown to be up-regulated in the UGS in response to androgen treatment [6,10,14,48,49]. It did not induce the expression of Foxa1 (Fig 7D), Ptc (Fig 7E), Bmp4 (Fig 7F) or Bmp7 (Fig 7H). Inhibiting ornithine decarboxylase with DFMO in the presence of testosterone significantly down-regulated Nkx3.1 (Fig 7A) and Notch1 (Fig 7G) expression, but did not affect the expression of other factors that were induced by testosterone. The inhibition of certain pathways and not all pathways in prostatic bud formation suggests that polyamines are required for specific pathways, and does not affect global growth and/or differentiation of the urogenital epithelium.


Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate.

Gamat M, Malinowski RL, Parkhurst LJ, Steinke LM, Marker PC - PLoS ONE (2015)

Markers of prostatic budding in cultured UGS tissues.E16 UGS tissues were cultured in the control media, testosterone supplemented media or media with T+DFMO. Testosterone induced the expression of Nkx3.1 (A), Sox9 (B), Wif1 (C), Notch1 (H) and Srd5a2 (J). It did not induce the expression of Foxa1 (D), Shh (E), Ptc (F), Bmp4 (G) or Bmp7 (I). Culturing the UGS in T+DFMO significantly decreased expression of Nkx3.1 (A) and Notch1 (H). * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4591331&req=5

pone.0139522.g007: Markers of prostatic budding in cultured UGS tissues.E16 UGS tissues were cultured in the control media, testosterone supplemented media or media with T+DFMO. Testosterone induced the expression of Nkx3.1 (A), Sox9 (B), Wif1 (C), Notch1 (H) and Srd5a2 (J). It did not induce the expression of Foxa1 (D), Shh (E), Ptc (F), Bmp4 (G) or Bmp7 (I). Culturing the UGS in T+DFMO significantly decreased expression of Nkx3.1 (A) and Notch1 (H). * p<0.05.
Mentions: Prostatic bud initial outgrowth is induced by androgens and coincides with up-regulation of genes. Inhibiting ornithine decarboxylase activity clearly affected prostatic bud formation, so we examined some of the pathways involved in prostatic bud initiation. Testosterone treatment significantly induced the expression of Nkx3.1 (Fig 7A), Sox9 (Fig 7B), Wif1 (Fig 7C), Notch1 (Fig 7G) and Srd5a2 (Fig 7I), which have previously been shown to be up-regulated in the UGS in response to androgen treatment [6,10,14,48,49]. It did not induce the expression of Foxa1 (Fig 7D), Ptc (Fig 7E), Bmp4 (Fig 7F) or Bmp7 (Fig 7H). Inhibiting ornithine decarboxylase with DFMO in the presence of testosterone significantly down-regulated Nkx3.1 (Fig 7A) and Notch1 (Fig 7G) expression, but did not affect the expression of other factors that were induced by testosterone. The inhibition of certain pathways and not all pathways in prostatic bud formation suggests that polyamines are required for specific pathways, and does not affect global growth and/or differentiation of the urogenital epithelium.

Bottom Line: Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens.DFMO also significantly decreased the expression of developmental regulatory gene Notch1.Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, United States of America.

ABSTRACT
The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

No MeSH data available.


Related in: MedlinePlus