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Interrelation of aromatase, estrogen receptor alpha and progesterone receptor in the developing mouse fetal brain

Year 2013, Volume: 38 Issue: 2, 174 - 180, 01.06.2013

Abstract

Purpose: Aromatase (Cyp19a1) is crucial for the sexually dimorphic development of the fetal brain, regulation of gonadotropin secretion and sexual interest in adults. Our goal is to determine the developmental mRNA expression patterns of aromatase, estrogen receptor alpha (Esr1) and progesterone receptor (Pgr) in the fetal mouse brain at different times of gestation. Methods: Female mice were mated with fertile males and checked for vaginal plug the next day to confirm successful mating (vaginal plug=day 1 of pregnancy). At gestational days 9-12-15-17-19-21 pregnant mice were sacrificed and fetal brains were removed and mRNAs were isolated and reverse transcribed into cDNAs. In order to evaluate mRNA expression levels, real time PCR was performed employing primers for Cyp19a1, Esr1 and Pgr genes. Results: In our studies, Esr1 and Pgr mRNA expression levels peaked at day 9 and returned to normal adult levels at around day 17-18. Cyp19a1 mRNA expression peaked at day 14-16 along with a drastic decrease in Esr1 and Pgr mRNA expression levels and then returned to normal adult levels around the time of delivery. Conclusion: Cyp19a1 expression in the fetal brain launches around gestational day 11-12 and peaks around gestational day 14-16 and fall back to normal adult levels at around gestational day 19-20. It has been recently reported that Esr1 and Pgr both mediate Cyp19a1 mRNA expression in the mouse brain. Together with these previous reports, our findings may imply that both Esr1 and Pgr possibly play a role in the developmental regulation of aromatase in the fetal mouse brain.

References

  • Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, and Wise PM. Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocr Rev. 2006; 27:575-605.
  • Wrobel B and Karasek M. Human sexuality and sex steroids. Neuro Endocrinol Lett. 2008; 29:3-10.
  • Bernardi F, Pluchino N, Stomati M, Pieri M, and Genazzani AR. CNS: sex steroids and SERMs. Ann N Y Acad Sci. 2003; 997:378-88.
  • Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, and Deb S. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005; 57:359-83.
  • Zhao H, Innes J, Brooks DC, Reierstad S, Yilmaz MB, Lin Z, and Bulun SE. A novel promoter controls Cyp19a1 gene expression in mouse adipose tissue. Reprod Biol Endocrinol. 2009; 7:37.
  • Golovine K, Schwerin M, and Vanselow J. Three different promoters control expression of the aromatase cytochrome p450 gene (cyp19) in mouse gonads and brain. Biol Reprod. 2003; 68:978-84.
  • Jones ME, Boon WC, Proietto J, and Simpson ER. Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol Metab. 2006; 17:55-64.
  • Murata Y, Robertson KM, Jones ME, and Simpson ER. Effect of estrogen deficiency in the male: the ArKO mouse model. Mol Cell Endocrinol. 2002; 193:7-12.
  • Zirilli L, Rochira V, Diazzi C, Caffagni G, and Carani C. Human models of aromatase deficiency. J Steroid Biochem Mol Biol. 2008; 109:212-8.
  • Belgorosky A, Guercio G, Pepe C, Saraco N, and Rivarola MA. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res. 2009; 72:321-30.
  • Simpson ER and Jones ME. Of mice and men: the many guises of estrogens. Ernst Schering Found Symp Proc. 2006; 45-67.
  • Balthazart J, Baillien M, and Ball GF. Phosphorylation processes mediate rapid changes of brain aromatase activity. J Steroid Biochem Mol Biol. 2001; 79:261-77.
  • Balthazart J, Baillien M, and Ball GF. Interactions between kinases and phosphatases in the rapid control of brain aromatase. J Neuroendocrinol. 2005; 17:553-9.
  • Yilmaz MB, Wolfe A, Cheng YH, Glidewell-Kenney C, Jameson JL, and Bulun SE. Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines. Biol Reprod. 2009; 81:956-65.
  • Yilmaz MB, Wolfe A, Zhao H, Brooks DC, and Bulun SE. Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines. J Mol Endocrinol. 2011; 47:69-80.
  • Abe-Dohmae S, Tanaka R, Takagi Y, and Harada N. In vitro increase of aromatase mRNA in diencephalic neurons. Neuroendocrinology. 1996; 63:46-52.
  • Hutchison JB, Beyer C, Hutchison RE, and Wozniak A. Sexual dimorphism in the developmental regulation of brain aromatase. J Steroid Biochem Mol Biol. 1995; 53:307-13.
  • Yazışma Adresi / Address for Correspondence: Dr. Mehmet Bertan Yılmaz Çukurova Üniversitesi Tıp Fakültesi Tıbbi Biyoloji ve Genetik Anabilim Dalı ADANA Tel: 0322 3386060/3498 e-mail: mehmetbertanyilmaz@gmailo.com geliş tarihi/received :09.08.2012 kabul tarihi/accepted:05.10.2012

Gelişmekte Olan Fare Fetüs Beyninde Aromataz, Östrojen Reseptör Alfa ve Progesteron Reseptörünün Birbirleriyle Olan İlişkileri

Year 2013, Volume: 38 Issue: 2, 174 - 180, 01.06.2013

Abstract

Amaç: Bu çalışmadaki amacımız, gonodotropin salgılanması, cinsel dimorfik fetal beyin gelişimi ve yetişkinlerdeki cinsel tercih için çok önemli olan, aromatazın ve östrojen reseptör alfa (Esr1) ve progesteron reseptörlerinin (Pgr) gebeliğin farklı dönemlerindeki mRNA ekspresyon profillerinin eş zamanlı olarak belirlenmesidir. Yöntem: Dişi fareler, üreme potansiyeli olan erkek farelerle çiftleştirildi ve başarılı çiftleşme, bir gün sonra oluşan vajinal plak kontrol edilerek doğrulandı (vajinal plak=gebeliğin birinci günü). Gebeliğin 9-12-15-17-19-21. günlerinde gebe farelerin yaşamları sonlandırıldı ve fetüslere ait beyinler çıkarılarak mRNA izole edildi ve cDNA haline çevrildi. mRNA ekspresyon düzeylerinin belirlenmesi Cyp19a1, Esr1 ve Pgr genlerine özgün primerler ile real time PCR yöntemi kullanılarak gerçekleştirildi. Bulgular: Çalışmalarımızda; Esr1 ve Pgr mRNA ekspresyon düzeyleri 9. günde tepe noktaya ulaştı, 17-18. günlerde ise normal yetişkin düzeylerine döndü. Cyp19a1 mRNA ekspresyonu, Esr1 ve Pgr mRNA düzeylerindeki ciddi bir azalmayla beraber, 15-16. günde tepe noktaya ulaştı ve takriben doğumun olacağı dönemlerde normal erişkin seviyelerine indi. Sonuç: Fetal beyinde Cyp19a1 ekspresyonu gebeliğin 11-12. günü civarında başlar ve 15-16. günlerinde tepe noktasına ulaşır. Bunu takiben 19-20. günlerinde de normal yetişkin seviyelerine iner. Son zamanlarda rapor edilen çalışmalarda, Esr1 ve Pgr"nin fare beyninde Cyp19a1 mRNA ekspresyonunun düzenlenmesinde rol oynadığı belirtilmiştir. Bu çalışmalar ışığında bizim bulgularımız, Esr1 ve Pgr"nin fetal fare beyninde aromataz ekspresyonun düzenlenmesinde rol oynadığını düşündürebilir.

References

  • Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, and Wise PM. Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocr Rev. 2006; 27:575-605.
  • Wrobel B and Karasek M. Human sexuality and sex steroids. Neuro Endocrinol Lett. 2008; 29:3-10.
  • Bernardi F, Pluchino N, Stomati M, Pieri M, and Genazzani AR. CNS: sex steroids and SERMs. Ann N Y Acad Sci. 2003; 997:378-88.
  • Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, and Deb S. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005; 57:359-83.
  • Zhao H, Innes J, Brooks DC, Reierstad S, Yilmaz MB, Lin Z, and Bulun SE. A novel promoter controls Cyp19a1 gene expression in mouse adipose tissue. Reprod Biol Endocrinol. 2009; 7:37.
  • Golovine K, Schwerin M, and Vanselow J. Three different promoters control expression of the aromatase cytochrome p450 gene (cyp19) in mouse gonads and brain. Biol Reprod. 2003; 68:978-84.
  • Jones ME, Boon WC, Proietto J, and Simpson ER. Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol Metab. 2006; 17:55-64.
  • Murata Y, Robertson KM, Jones ME, and Simpson ER. Effect of estrogen deficiency in the male: the ArKO mouse model. Mol Cell Endocrinol. 2002; 193:7-12.
  • Zirilli L, Rochira V, Diazzi C, Caffagni G, and Carani C. Human models of aromatase deficiency. J Steroid Biochem Mol Biol. 2008; 109:212-8.
  • Belgorosky A, Guercio G, Pepe C, Saraco N, and Rivarola MA. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res. 2009; 72:321-30.
  • Simpson ER and Jones ME. Of mice and men: the many guises of estrogens. Ernst Schering Found Symp Proc. 2006; 45-67.
  • Balthazart J, Baillien M, and Ball GF. Phosphorylation processes mediate rapid changes of brain aromatase activity. J Steroid Biochem Mol Biol. 2001; 79:261-77.
  • Balthazart J, Baillien M, and Ball GF. Interactions between kinases and phosphatases in the rapid control of brain aromatase. J Neuroendocrinol. 2005; 17:553-9.
  • Yilmaz MB, Wolfe A, Cheng YH, Glidewell-Kenney C, Jameson JL, and Bulun SE. Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines. Biol Reprod. 2009; 81:956-65.
  • Yilmaz MB, Wolfe A, Zhao H, Brooks DC, and Bulun SE. Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines. J Mol Endocrinol. 2011; 47:69-80.
  • Abe-Dohmae S, Tanaka R, Takagi Y, and Harada N. In vitro increase of aromatase mRNA in diencephalic neurons. Neuroendocrinology. 1996; 63:46-52.
  • Hutchison JB, Beyer C, Hutchison RE, and Wozniak A. Sexual dimorphism in the developmental regulation of brain aromatase. J Steroid Biochem Mol Biol. 1995; 53:307-13.
  • Yazışma Adresi / Address for Correspondence: Dr. Mehmet Bertan Yılmaz Çukurova Üniversitesi Tıp Fakültesi Tıbbi Biyoloji ve Genetik Anabilim Dalı ADANA Tel: 0322 3386060/3498 e-mail: mehmetbertanyilmaz@gmailo.com geliş tarihi/received :09.08.2012 kabul tarihi/accepted:05.10.2012
There are 18 citations in total.

Details

Primary Language Turkish
Journal Section Research
Authors

Mehmet Bertan Yılmaz This is me

Mehmet Ali Erkoç This is me

Sabriye Kocatürk-sel This is me

Erdal Tunç This is me

Lütfiye Özpak This is me

Ayfer Pazarbaşı This is me

Ali İrfan Güzel This is me

Davut Alptekin This is me

Hüsnü Ümit Lüleyap This is me

Osman Demirhan This is me

Mülkiye Kasap This is me

Halil Kasap This is me

Publication Date June 1, 2013
Published in Issue Year 2013 Volume: 38 Issue: 2

Cite

MLA Yılmaz, Mehmet Bertan et al. “Gelişmekte Olan Fare Fetüs Beyninde Aromataz, Östrojen Reseptör Alfa Ve Progesteron Reseptörünün Birbirleriyle Olan İlişkileri”. Cukurova Medical Journal, vol. 38, no. 2, 2013, pp. 174-80.