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• W2071707735 abstract "The murine epididymis synthesizes and secretes a retinoic acid-binding protein (mE-RABP) that belongs to the lipocalin superfamily. The gene encoding mE-RABP is specifically expressed in the mouse mid/distal caput epididymidis under androgen control. In transgenic mice, a 5-kilobase pair (kb) promoter fragment, but not a 0.6-kb fragment, of the mE-RABP gene driving the chloramphenicol acetyltransferase (CAT) reporter gene restricted high level of transgene expression to the caput epididymidis. No transgene expression was detected in any other male or female tissues. Immunolocalization of the CAT protein and in situ hybridization of the corresponding CAT mRNA indicated that transgene expression occurred in the principal cells of the mid/distal caput epididymidis, thereby mimicking the spatial endogenous mE-RABP gene expression. Transgene and mE-RABP gene expression was detected from 30 days and progressively increased until 60 days of age. Castration, efferent duct ligation, and hormone replacement studies demonstrated that transgene expression was specifically regulated by androgen but not by any other testicular factors. Altogether, our results demonstrate that the 5-kb promoter fragment of the mE-RABP gene contains all of the information required for the hormonal regulation and the spatial and temporal expression of the mE-RABP gene in the epididymis. The murine epididymis synthesizes and secretes a retinoic acid-binding protein (mE-RABP) that belongs to the lipocalin superfamily. The gene encoding mE-RABP is specifically expressed in the mouse mid/distal caput epididymidis under androgen control. In transgenic mice, a 5-kilobase pair (kb) promoter fragment, but not a 0.6-kb fragment, of the mE-RABP gene driving the chloramphenicol acetyltransferase (CAT) reporter gene restricted high level of transgene expression to the caput epididymidis. No transgene expression was detected in any other male or female tissues. Immunolocalization of the CAT protein and in situ hybridization of the corresponding CAT mRNA indicated that transgene expression occurred in the principal cells of the mid/distal caput epididymidis, thereby mimicking the spatial endogenous mE-RABP gene expression. Transgene and mE-RABP gene expression was detected from 30 days and progressively increased until 60 days of age. Castration, efferent duct ligation, and hormone replacement studies demonstrated that transgene expression was specifically regulated by androgen but not by any other testicular factors. Altogether, our results demonstrate that the 5-kb promoter fragment of the mE-RABP gene contains all of the information required for the hormonal regulation and the spatial and temporal expression of the mE-RABP gene in the epididymis. murine epididymal retinoic acid-binding protein androgen-specific response region base pair(s) kilobase pair(s) chloramphenicol acetyltransferase polymerase chain reaction phosphate-buffered saline During their transit through the epididymis, spermatozoa undergo biochemical and morphological changes to acquire motility and the ability to fertilize an oocyte in vivo (1Bedford J.M. J. Exp. Zool. 1967; 166: 271-281Crossref PubMed Scopus (103) Google Scholar, 2Orgebin-Crist M.C. Nature. 1967; 216: 816-818Crossref PubMed Scopus (161) Google Scholar). The maturation process progresses along the epididymal duct and is believed to be dependent on epididymal secretory proteins.The epididymis displays a highly region-specific pattern of gene expression. However, little is known regarding the molecular mechanisms that are involved in the regulation of tissue- and region-specific gene expression. Gene expression in the epididymis is mainly under androgen control (for review, see Ref. 3Orgebin-Crist M.C. Bhasin D. Gabelnick H.L. Spieler J.M. Swerdloff R.S. Wang C. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss Inc., New York1996: 27-38Google Scholar). Indeed, androgen withdrawal, either by orchiectomy or by hypophysectomy, prevents the sperm maturation process (4Orgebin-Crist M.C. Tichenor P.L. Nature. 1973; 245: 328-329Crossref PubMed Scopus (32) Google Scholar, 5Dyson A.L. Orgebin-Crist M.C. Endocrinology. 1973; 93: 391-402Crossref PubMed Scopus (141) Google Scholar). However, testicular factors (6Douglass J. Garrett S.H. Garrett J.E. Ann. N. Y. Acad. Sci. 1991; 637: 384-398Crossref PubMed Scopus (31) Google Scholar), estrogen (7Toney T.W. Danzo B.J. Endocrinology. 1989; 125: 243-249Crossref PubMed Scopus (19) Google Scholar), growth factors (8Lan Z.J. Labus J.C. Hinton B.T. Biol. Reprod. 1998; 58: 197-206Crossref PubMed Scopus (82) Google Scholar), and retinoic acid (9Astraudo C. Lefevre A. Boue F. Durr F. Finaz C. Arch. Androl. 1995; 35: 247-259Crossref PubMed Scopus (9) Google Scholar) have also been demonstrated to be involved in epididymis-specific gene expression. Whether these endocrine and paracrine signal pathways cooperate to restrict gene expression to a narrow segment of the epididymal duct is unclear.We previously described two proteins (major and minor forms) that are generated by the differential cleavage of a unique precursor, initially named mouse epididymal protein 10 (10Rankin T.L. Tsuruta K.J. Holland M.K. Griswold M.D. Orgebin-Crist M.C. Biol. Reprod. 1992; 46: 747-766Crossref PubMed Scopus (103) Google Scholar). This protein, recently renamed murine epididymal retinoic acid-binding protein (mE-RABP)1 (11Lareyre J.J. Zheng W.L. Zhao G.Q. Kasper S. Newcomer M.E. Matusik R.J. Ong D.E. Orgebin-Crist M.C. Endocrinology. 1998; 139: 2971-2981Crossref PubMed Scopus (44) Google Scholar), is specifically synthesized and secreted by the principal cells of the distal caput epididymidis. The mE-RABP protein binds active retinoids (9-cis- and all-trans-retinoic acid) but not retinol (12Rankin T.L. Ong D.E. Orgebin-Crist M.C. Biol. Reprod. 1992; 46: 767-771Crossref PubMed Scopus (31) Google Scholar) and is the orthologue of two other retinoic acid-binding proteins described in the rat epididymis. These rat proteins were successively named B/C (13Brooks D.E. Means A.R. Wright E.J. Singh S.P. Tiver K.K. J. Biol. Chem. 1986; 261: 4956-4961Abstract Full Text PDF PubMed Google Scholar), EBP 1 and EBP 2 (14Ong D.E. Chytil F. Arch. Biochem. Biophys. 1988; 267: 474-478Crossref PubMed Scopus (36) Google Scholar), E-RABP (15Newcomer M.E. Ong D.E. J. Biol. Chem. 1990; 265: 12876-12879Abstract Full Text PDF PubMed Google Scholar), and ESP I (16Girotti M. Jones R. Emery D.C. Chia W. Hall L. Biochem. J. 1992; 281: 203-210Crossref PubMed Scopus (45) Google Scholar). Analysis of the amino acid sequence and putative three-dimensional structure show that mE-RABP belongs to the lipocalin superfamily (11Lareyre J.J. Zheng W.L. Zhao G.Q. Kasper S. Newcomer M.E. Matusik R.J. Ong D.E. Orgebin-Crist M.C. Endocrinology. 1998; 139: 2971-2981Crossref PubMed Scopus (44) Google Scholar).The mE-RABP protein is encoded by a single-copy gene localized to the [A3-B] region of mouse chromosome 2, a region rich in genes encoding lipocalin and displaying a similar genomic structure to that of the mE-RABP gene (17Lareyre J.J. Mattei M.-G. Kasper S. Ong D.E. Matusik R.J. Orgebin-Crist M.-C. Mol. Reprod. Dev. 1998; 50: 387-395Crossref PubMed Scopus (18) Google Scholar).The mE-RABP gene expression is androgen-regulated in vivo(11Lareyre J.J. Zheng W.L. Zhao G.Q. Kasper S. Newcomer M.E. Matusik R.J. Ong D.E. Orgebin-Crist M.C. Endocrinology. 1998; 139: 2971-2981Crossref PubMed Scopus (44) Google Scholar). In addition, transient transfection studies have shown that a functional androgen-specific response region (ARR) is localized within the first 600 bp of the mE-RABP gene promoter (18.Lareyre, J. J., Kasper, S., Ong, D. E., Matusik, R. J., and Orgebin-Crist, M. C. (1998) Xth European Workshop on Molecular and Cellular Endocrinology of the Testis, Capri, Italy, March 28 to April 1, 1998 (Abstr. E14).Google Scholar). The androgen dependence and the strong tissue- and region-specific expression make the mE-RABP gene a good candidate to study the molecular mechanisms that restrict gene expression to a narrow segment of the epididymis under androgen control. In the absence of appropriate epididymal cell lines, cis-DNA regulatory elements involved in the tissue-specific and androgen-regulated expression of the mE-RABP gene can only be identified in transgenic mice.In the present study, we demonstrate that 5 kb of the 5′-flanking region of the mE-RABP gene can drive the specific expression of the chloramphenicol acetyltransferase (CAT) reporter gene to the principal cells of the mid/distal caput epididymidis, thereby mimicking the expression of the endogenous gene. We also demonstrate that the 5-kb DNA fragment contains most, if not all, of the information required for the temporal and hormonal regulation of the mE-RABP gene in vivo. During their transit through the epididymis, spermatozoa undergo biochemical and morphological changes to acquire motility and the ability to fertilize an oocyte in vivo (1Bedford J.M. J. Exp. Zool. 1967; 166: 271-281Crossref PubMed Scopus (103) Google Scholar, 2Orgebin-Crist M.C. Nature. 1967; 216: 816-818Crossref PubMed Scopus (161) Google Scholar). The maturation process progresses along the epididymal duct and is believed to be dependent on epididymal secretory proteins. The epididymis displays a highly region-specific pattern of gene expression. However, little is known regarding the molecular mechanisms that are involved in the regulation of tissue- and region-specific gene expression. Gene expression in the epididymis is mainly under androgen control (for review, see Ref. 3Orgebin-Crist M.C. Bhasin D. Gabelnick H.L. Spieler J.M. Swerdloff R.S. Wang C. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss Inc., New York1996: 27-38Google Scholar). Indeed, androgen withdrawal, either by orchiectomy or by hypophysectomy, prevents the sperm maturation process (4Orgebin-Crist M.C. Tichenor P.L. Nature. 1973; 245: 328-329Crossref PubMed Scopus (32) Google Scholar, 5Dyson A.L. Orgebin-Crist M.C. Endocrinology. 1973; 93: 391-402Crossref PubMed Scopus (141) Google Scholar). However, testicular factors (6Douglass J. Garrett S.H. Garrett J.E. Ann. N. Y. Acad. Sci. 1991; 637: 384-398Crossref PubMed Scopus (31) Google Scholar), estrogen (7Toney T.W. Danzo B.J. Endocrinology. 1989; 125: 243-249Crossref PubMed Scopus (19) Google Scholar), growth factors (8Lan Z.J. Labus J.C. Hinton B.T. Biol. Reprod. 1998; 58: 197-206Crossref PubMed Scopus (82) Google Scholar), and retinoic acid (9Astraudo C. Lefevre A. Boue F. Durr F. Finaz C. Arch. Androl. 1995; 35: 247-259Crossref PubMed Scopus (9) Google Scholar) have also been demonstrated to be involved in epididymis-specific gene expression. Whether these endocrine and paracrine signal pathways cooperate to restrict gene expression to a narrow segment of the epididymal duct is unclear. We previously described two proteins (major and minor forms) that are generated by the differential cleavage of a unique precursor, initially named mouse epididymal protein 10 (10Rankin T.L. Tsuruta K.J. Holland M.K. Griswold M.D. Orgebin-Crist M.C. Biol. Reprod. 1992; 46: 747-766Crossref PubMed Scopus (103) Google Scholar). This protein, recently renamed murine epididymal retinoic acid-binding protein (mE-RABP)1 (11Lareyre J.J. Zheng W.L. Zhao G.Q. Kasper S. Newcomer M.E. Matusik R.J. Ong D.E. Orgebin-Crist M.C. Endocrinology. 1998; 139: 2971-2981Crossref PubMed Scopus (44) Google Scholar), is specifically synthesized and secreted by the principal cells of the distal caput epididymidis. The mE-RABP protein binds active retinoids (9-cis- and all-trans-retinoic acid) but not retinol (12Rankin T.L. Ong D.E. Orgebin-Crist M.C. Biol. Reprod. 1992; 46: 767-771Crossref PubMed Scopus (31) Google Scholar) and is the orthologue of two other retinoic acid-binding proteins described in the rat epididymis. These rat proteins were successively named B/C (13Brooks D.E. Means A.R. Wright E.J. Singh S.P. Tiver K.K. J. Biol. Chem. 1986; 261: 4956-4961Abstract Full Text PDF PubMed Google Scholar), EBP 1 and EBP 2 (14Ong D.E. Chytil F. Arch. Biochem. Biophys. 1988; 267: 474-478Crossref PubMed Scopus (36) Google Scholar), E-RABP (15Newcomer M.E. Ong D.E. J. Biol. Chem. 1990; 265: 12876-12879Abstract Full Text PDF PubMed Google Scholar), and ESP I (16Girotti M. Jones R. Emery D.C. Chia W. Hall L. Biochem. J. 1992; 281: 203-210Crossref PubMed Scopus (45) Google Scholar). Analysis of the amino acid sequence and putative three-dimensional structure show that mE-RABP belongs to the lipocalin superfamily (11Lareyre J.J. Zheng W.L. Zhao G.Q. Kasper S. Newcomer M.E. Matusik R.J. Ong D.E. Orgebin-Crist M.C. Endocrinology. 1998; 139: 2971-2981Crossref PubMed Scopus (44) Google Scholar). The mE-RABP protein is encoded by a single-copy gene localized to the [A3-B] region of mouse chromosome 2, a region rich in genes encoding lipocalin and displaying a similar genomic structure to that of the mE-RABP gene (17Lareyre J.J. Mattei M.-G. Kasper S. Ong D.E. Matusik R.J. Orgebin-Crist M.-C. Mol. Reprod. Dev. 1998; 50: 387-395Crossref PubMed Scopus (18) Google Scholar). The mE-RABP gene expression is androgen-regulated in vivo(11Lareyre J.J. Zheng W.L. Zhao G.Q. Kasper S. Newcomer M.E. Matusik R.J. Ong D.E. Orgebin-Crist M.C. Endocrinology. 1998; 139: 2971-2981Crossref PubMed Scopus (44) Google Scholar). In addition, transient transfection studies have shown that a functional androgen-specific response region (ARR) is localized within the first 600 bp of the mE-RABP gene promoter (18.Lareyre, J. J., Kasper, S., Ong, D. E., Matusik, R. J., and Orgebin-Crist, M. C. (1998) Xth European Workshop on Molecular and Cellular Endocrinology of the Testis, Capri, Italy, March 28 to April 1, 1998 (Abstr. E14).Google Scholar). The androgen dependence and the strong tissue- and region-specific expression make the mE-RABP gene a good candidate to study the molecular mechanisms that restrict gene expression to a narrow segment of the epididymis under androgen control. In the absence of appropriate epididymal cell lines, cis-DNA regulatory elements involved in the tissue-specific and androgen-regulated expression of the mE-RABP gene can only be identified in transgenic mice. In the present study, we demonstrate that 5 kb of the 5′-flanking region of the mE-RABP gene can drive the specific expression of the chloramphenicol acetyltransferase (CAT) reporter gene to the principal cells of the mid/distal caput epididymidis, thereby mimicking the expression of the endogenous gene. We also demonstrate that the 5-kb DNA fragment contains most, if not all, of the information required for the temporal and hormonal regulation of the mE-RABP gene in vivo. We gratefully acknowledge the Vanderbilt Transgenic/ES cell Shared Resource for generating the transgenic mouse lines. We thank Drs. C. Pettepher and J. Wright for helpful advice throughout the course of these studies. We thank Dr. B. J. Danzo for critical comments on the manuscript. The DNA sequencing was performed by the Cancer Center DNA Sequencing Core, directed by Dr. K. Bhat." @default.
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• W2071707735 title "A 5-Kilobase Pair Promoter Fragment of the Murine Epididymal Retinoic Acid-binding Protein Gene Drives the Tissue-specific, Cell-specific, and Androgen-regulated Expression of a Foreign Gene in the Epididymis of Transgenic Mice" @default.
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