Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology

Regulation of protein tyrosine phosphatase 4a1, B-cell translocation gene 2, nuclear receptor subfamily 4a1 and diacylglycerol O-acyltransferase 1 by follicle stimulating hormone in the rat ovary

Jonathan Schmidt A , Jeanene de Avila A and Derek McLean A B

A Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164, USA.

B Corresponding author. Email:

Reproduction, Fertility and Development 18(7) 757-765
Submitted: 20 December 2005  Accepted: 28 May 2006   Published: 28 August 2006


Ovarian response to follicle stimulating hormone (FSH) and luteinising hormone (LH) leads to the formation of a mature follicle that is eventually ovulated. FSH and LH are essential for this process because they direct changes in somatic cells associated with folliculogenesis by regulating the expression of multiple genes. We hypothesised that genes induced by FSH in rat Sertoli cells would also show hormonal regulation during rat folliculogenesis. The objective of this study was to determine the expression patterns of diacylglycerol O-acyltransferase 1 (Dgat1), nuclear receptor subfamily 4a1 (Nr4a1), an anti-proliferative gene (Btg2) and a protein tyrosine phosphatase (Ptp4a1) in the ovaries of pregnant mare serum gonadotrophin (PMSG)-treated and human chorionic gonadotrophin (hCG)-treated rats. Expression of Dgat1, Nr4a1 and Ptp4a1 was induced in ovaries 4 h post PMSG treatment. When rats were treated with hCG, Dgat1, Nr4a1 and Ptp4a1 expression was induced by 12 h. Expression of Nr4a1 protein increases 12–24 h after induction of gene expression. Nr4a1 protein was observed in the granulosa, theca and luteal cells post PMSG and hCG treatment. These findings should increase our knowledge of mechanisms regulating folliculogenesis and luteinisation and demonstrate the diverse proteins that are important in ovarian function.


Bagnato C.Igal A. R.2003Overexpression of diacylglycerol acyltransferase-1 reduces phospholipid synthesis, proliferation, and invasiveness in simian virus 40-transformed human lung fibroblasts.J. Biol. Chem.27852 20352 211doi:10.1074/JBC.M305760200Pubmed Abstract

Bradbury A.Possenti R.Shooter E. M.Tirone F.1991Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization.Proc. Natl Acad. Sci. USA8833533357doi:10.1073/PNAS.88.8.3353Pubmed Abstract

Corbin T. J.McCabe J. G.2002Strain variation of immature female rats in response to various superovulatory hormone preparations and routes of administration.Contemp. Top. Lab. Anim. Sci.411823Pubmed Abstract

Diamond R. H.Cressman D. E.Laz T. M.Abrams C. S.Taub R.1994PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth.Mol. Cell. Biol.1437523762Pubmed Abstract

Diamond R. H.Peters C.Jung S. P.Greenbaum L. E.Haber B. A.Silberg D. G.Traber P. G.Taub R.1996Expression of PRL-1 nuclear PTPase is associated with proliferation in liver but with differentiation in intestine.Am. J. Physiol.271G121G129Pubmed Abstract

Gilbert G. S., and Roy S. K. (1993). Follicular development and its control. In ‘The Physiology of Reproduction’, 2nd edn. (Eds E. Knobil and J. D. Neill.) pp. 629–724. (Raven Press: New York, NY, USA.)

Gonzalez-Robayna I. J.Alliston T. N.Buse P.Firestone G. L.Richards J. S.1999Functional and subcellular changes in the A-kinase-signaling pathway: relation to aromatase and Sgk expression during the transition of granulosa cells to luteal cells.Mol. Endocrinol.1313181337doi:10.1210/ME.13.8.1318Pubmed Abstract

Gonzalez-Robayna I. J.Falender A. E.Ochsner S.Firestione G. L.Richards J. S.2000Follicle-stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-induced kinase (sgk): Evidence for A kinase-independent signaling by FSH in granulosa cells.Mol. Endocrinol.1412831300doi:10.1210/ME.14.8.1283Pubmed Abstract

Guigon C. J.Coudouel N.Mazaud-Guittot S.Forest M. G.Magre S.2005Follicular cells acquire Sertoli cell characteristics after oocyte loss.Endocrinology14629923004doi:10.1210/EN.2005-0045Pubmed Abstract

Guo S.Russo I. H.Russo J.2003Difference in gene expression profile in breast epithelial cells from women with different reproductive history.Int. J. Oncol.23933941Pubmed Abstract

Havelock J. C.Smith A. L.Seely J. B.Dooley C. A.Rodgers R. J.Rainey W. E.Carr B. R.2005The NGFI-B family of transcription factors regulates expression of 3beta-hydroxysteroid dehydrogenase type 2 in the human ovary.Mol. Hum. Reprod.117985doi:10.1093/MOLEHR/GAH139Pubmed Abstract

Homa S. T.Racowsky C.McGaughey R. W.1986Lipid analysis of immature pig oocytes.J. Reprod. Fertil.77425434Pubmed Abstract

Jo M.Gieske M. C.Payne C. E.Wheeler-Price S. E.Gieske J. B.Ignatius I. V.Curry T. E.JrKo C.2004Development and application of a rat ovarian gene expression database.Endocrinology14553845395doi:10.1210/EN.2004-0407Pubmed Abstract

Leo C.Pisarska M. D.Hsueh A. J. W.2001DNA array analysis of changes in preovulatory gene expression in the rat ovary.Biol. Reprod.65269276

Livneh E.Fishman D. D.1997Linking protein kinase C to cell-cycle control.Eur. J. Biochem.24819
doi:10.1111/J.1432-1033.1997.T01-4-00001.XPubmed Abstract

Martin L. J.Tremblay J. J.2005The human 3β-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase type 2 promoter is a novel target for the immediate early orphan nuclear receptor Nur77 in steroidogenic cells.Endocrinology146861869doi:10.1210/EN.2004-0859Pubmed Abstract

Mayorek N.Grinstein I.Bar-Tana J.1989Triacylglycerol synthesis in cultured rat hepatocytes. The rate-limiting role of diacylglycerol acyltransferase.Eur. J. Biochem.182395400doi:10.1111/J.1432-1033.1989.TB14844.XPubmed Abstract

McLean D. J.Friel P. J.Pouchnik D.Griswold M. D.2002Oligonucleotide microarray analysis of gene expression in follicle-stimulating hormone-treated rat Sertoli cells.Mol. Endocrinol.1627802792doi:10.1210/ME.2002-0059Pubmed Abstract

Milbrandt J.1988Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene.Neuron1183188doi:10.1016/0896-6273(88)90138-9Pubmed Abstract

Montagnoli A.Guardavaccaro D.Starace G.Tirone F.1996Overexpression of the nerve growth factor-inducible PC3 immediate early gene is associated with growth inhibition.Cell Growth Differ.713271336Pubmed Abstract

Mueller L.Broering D. C.Meyer J.Vashist Y.Goettsche J.Wilms C.Rogiers X.2002The induction of the immediate-early-genes Egr-1, PAI-1 and PRL-1 during liver regeneration in surgical models is related to increased portal flow.J. Hepatol.37606612doi:10.1016/S0168-8278(02)00238-6Pubmed Abstract

Muller P. Y.Janovjak H.Miserez A. R.Dobbie Z.2002Processing of gene expression data generated by quantitative real-time RT-PCR.Biotechniques3213721379Pubmed Abstract

Nishizuka Y.1992Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.Science258607614Pubmed Abstract

Orth J. M.1984The role of follicle-stimulating hormone in controlling Sertoli cell proliferation in testes of fetal rats.Endocrinology11512481255Pubmed Abstract

Park S. Y.Jameson L.2005Minireview: transcriptional regulation of gonadal development and differentiation.Endocrinology14610351042doi:10.1210/EN.2004-1454Pubmed Abstract

Park J.-I.Park H.-J.Choi H.-S.Lee K.Lee W.-K.Chun S.-Y.2001Gonadotropin regulation of NGFI-B messenger ribonucleic acid expression during ovarian follicle development in the rat.Endocrinology14230513059doi:10.1210/EN.142.7.3051Pubmed Abstract

Park J.-I.Park H.-J.Lee Y.-I.Seo Y.-M.Chun S.-Y.2003Regulation of NGFI-B expression during the ovulatory process.Mol. Cell. Endocrinol.2022529Pubmed Abstract

Peng Y.Du K.Ramirez S.Diamond R. H.Taub R.1999Mitogenic up-regulation of the PRL-1 protein tyrosine phosphatase gene by Egr-1.J. Biol. Chem.27445134520doi:10.1074/JBC.274.8.4513Pubmed Abstract

Richards J. S.1994Hormonal control of gene expression in the ovary.Endocr. Rev.15725751doi:10.1210/ER.15.6.725Pubmed Abstract

Richards J. S.2001aPerspective: The ovarian follicle—A perspective in 2001.Endocrinology14221842193doi:10.1210/EN.142.6.2184Pubmed Abstract

Richards J. S.2001bNew signaling pathways for hormones and cyclic adenosine 3′,5′-monophosphate action in endocrine cells.Mol. Endocrinol.15209218doi:10.1210/ME.15.2.209Pubmed Abstract

Richards J. S.Russell D. L.Ochsner S.Hsieh M.Doyle K. H.Falender A. E.Lo Y. K.Sharma S. C.2002Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization.Recent Prog. Horm. Res.57195220doi:10.1210/RP.57.1.195Pubmed Abstract

Robker R. L.Richards J. S.1998Hormonal control of the cell cycle in ovarian cells: Proliferation versus differentiation.Biol. Reprod.59476482doi:10.1095/BIOLREPROD59.3.476

Russell D. L.Doyle K. M. H.Gonzales-Robayna I.Pipaon C.Richards J. S.2003Egr-1 induction in rat granulosa cells by follicle-stimulating hormone and luteinizing hormone: Combinatorial regulation by transcription factors cyclic adenosine 3′,5′-monophosphate regulatory element binding protein, serum response factor, Sp1, and early growth response factor-1.Mol. Endocrinol.17520533doi:10.1210/ME.2002-0066Pubmed Abstract

Sasson R.Dantes A.Tajima K.Amsterdam A.2003Novel genes modulated by FSH in normal and immortalized FSH-responsive cells: new insights into the mechanism of FSH action.FASEB J.1712561266doi:10.1096/FJ.02-0740COMPubmed Abstract

Singh J.Handelsman D. J.1996Neonatal administration of FSH increases Sertoli cell numbers and spermatogenesis in gonadotropin-deficient (hpg) mice.J. Endocrinol.1513748doi:10.1677/JOE.0.1510037Pubmed Abstract

Song K.-H.Park J.-I.Lee M.-O.Soh J.Lee K.Choi H.-S.2001LH induces orphan nuclear receptor Nur77 gene expression in testicular Leydig cells.Endocrinology14251165123doi:10.1210/EN.142.12.5116Pubmed Abstract

Song K.-H.Lee K.Choi H.-S.2002Endocrine disrupter bisphenol A induces orphan nuclear receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells.Endocrinology14322082215doi:10.1210/EN.143.6.2208Pubmed Abstract

Stocco C. O.Zhong L.Sugimoto Y.Ichikawa A.Lau L. F.Gibori G.2000Prostaglandin F2α-induced expression of 20α-hydroxysteroid dehydrogenase involves the transcription factor NUR77.J. Biol. Chem.27537 20237 211doi:10.1074/JBC.M006016200Pubmed Abstract

Stocco C. O.Laus L. F.Gigori G.2002A calcium/calmodulin-dependent activation of ERK1/2 mediates Jun D phosphorylation and induction of nur77 and 20α-hsd genes by prostaglandin F2α in ovarian cells. J. Biol. Chem.27732933302doi:10.1074/JBC.M110936200Pubmed Abstract

Tirone F.2001The gene PC3TIS21/BTG2, prototype member of the PC3/BTG/TOB family: regulator in control of cell growth, differentiation, and DNA repair?J. Cell. Physiol.187155165doi:10.1002/JCP.1062Pubmed Abstract

Wang J.Kirby C. E.Herbst R.2002The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis.J. Biol. Chem.27746 65946 668doi:10.1074/JBC.M206407200Pubmed Abstract

Werner S. R.Lee P. A.DeCamp M. W.Crowell D. N.Randall S. K.Crowell P. L.2003Enhanced cell cycle progression and down regulation of p21 (Cip1/Waf1) by Prl tyrosine phosphatases.Cancer Lett.202201211doi:10.1016/S0304-3835(03)00517-2Pubmed Abstract

Wilson T. E.Fahrner T. J.Johnston M.Milbrandt J.1991Identification of the DNA binding site for NGFI-B by genetic selection in yeast.Science25212961300Pubmed Abstract

Wilson T. E.Mouw A. R.Weaver C. A.Milbrandt J.Parker K. L.1993The orphan nuclear receptor NGFI-G regulates expression of the gene encoding steroid 21-hydroxylase.Mol. Cell. Biol.13861868Pubmed Abstract

Wu Y.Ghosh S.Nishi Y.Yanase T.Nawata H.Hu Y.2005The orphan nuclear receptors NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulosa cells: A possible mechanism for repression of aromatase expression upon luteinizing hormone surge.Endocrinology146237246doi:10.1210/EN.2004-0889Pubmed Abstract

Zhao Z.Lee C.-C.Monckton D. G.Yazdani A.Coolbaugh M. I.Li X.Bailey J.Shen Y.Caskey T.1996Characterization and genomic mapping of genes and pseudogenes of a new human protein tyrosine phosphatase.Genomics35172181doi:10.1006/GENO.1996.0336Pubmed Abstract

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