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• W2022787977 abstract "The Pem gene encodes an atypical homeodomain protein, distantly related to Prd/Pax family members, that we demonstrate is regulated in a complex transcriptional and post-transcriptional manner. We show that the rat Pem genomic structure includes three 5′-untranslated (5′-UT) exons and four coding exons, three of which encode the homeodomain. Several alternatively spliced transcripts were identified, including one that skips an internal coding exon, enabling this mRNA to express a novel form of the Pem protein. Other alternatively spliced mRNAs were characterized that possess different 5′-UT regions, including a muscle-specific transcript. The different 5′-UT termini present in Pem transcripts conferred different levels of translatability in vitro. Two promoters containing multiple transcription initiation sites were identified: a distal promoter (Pd) in the first 5′-UT exon and a proximal promoter (Pp) located in the “intron” upstream of the first coding exon. The Pd was active in placenta, ovary, tumor cell lines, and to a lesser extent in skeletal muscle. In contrast, transcripts from the Pp were only detectable in testis and epididymis and were only expressed in epididymis in the presence of testosterone. To our knowledge no transcription factors have previously been identified that exhibit androgen-dependent expression in the epididymis. The Pem gene encodes an atypical homeodomain protein, distantly related to Prd/Pax family members, that we demonstrate is regulated in a complex transcriptional and post-transcriptional manner. We show that the rat Pem genomic structure includes three 5′-untranslated (5′-UT) exons and four coding exons, three of which encode the homeodomain. Several alternatively spliced transcripts were identified, including one that skips an internal coding exon, enabling this mRNA to express a novel form of the Pem protein. Other alternatively spliced mRNAs were characterized that possess different 5′-UT regions, including a muscle-specific transcript. The different 5′-UT termini present in Pem transcripts conferred different levels of translatability in vitro. Two promoters containing multiple transcription initiation sites were identified: a distal promoter (Pd) in the first 5′-UT exon and a proximal promoter (Pp) located in the “intron” upstream of the first coding exon. The Pd was active in placenta, ovary, tumor cell lines, and to a lesser extent in skeletal muscle. In contrast, transcripts from the Pp were only detectable in testis and epididymis and were only expressed in epididymis in the presence of testosterone. To our knowledge no transcription factors have previously been identified that exhibit androgen-dependent expression in the epididymis. INTRODUCTIONAndrogens are of paramount importance to spermatogenesis in the testis and sperm maturation in the epididymis. Testosterone alone maintains spermatogenesis in gonadotropin-deficient animals, including hypophysectomized rats and mutant hypogonadal mice (1Santulli R. Sprando R.L. Awoniyi C.A. Ewing L.L. Zirken B.R. Endocrinology. 1990; 126: 95-101Crossref PubMed Scopus (52) Google Scholar, 2Sun Y. Wreford N.G. Robertson D.M. de Kretser D.M. Endocrinology. 1990; 127: 1215-1223Crossref PubMed Scopus (98) Google Scholar, 3Singh J. O'Neill C. Handelsman D.J. Endocrinology. 1995; 136: 5311-5321Crossref PubMed Google Scholar). Evidence suggests that testosterone drives spermatogenesis by acting on Sertoli cells and peritubular cells, both of which express androgen receptors (4Sar M. Hall S.H. Wilson E.M. French F.S. Russell L.D. Griswold M.D. The Sertoli Cell. Cache River Press, Clearwater, FL1993: 510Google Scholar, 5Norton J.N. Skinner M.K. Endocrinology. 1989; 124: 2711-2719Crossref PubMed Scopus (60) Google Scholar). Sertoli cells perform numerous functions critical for spermatogenesis by virtue of their intimate contact with differentiating germ cells within the seminiferous tubule. Androgens have been known to be critical for epididymal function since early in this century. They regulate the proliferation and differentiation of somatic cells in the epididymis and control the microenvironment of the maturing spermatozoa by regulating the synthesis of adhesion proteins in the epididymis, the secretion of proteins into the luminal fluid that are in contact with the spermatozoa, and the transport of ions and small organic molecules across the epididymal epithelium (6Robarie B. Hermo L. Knobil E. Neill J. The Physiology of Reproduction. Raven Press, New York1988: 999Google Scholar, 7Orgebin-Crist M.-C. (Bhasin S. Swevdloff R.S. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss, Inc., NY1996Google Scholar). Secreted proteins under androgen control in the epididymis include steroid-metabolizing enzymes, polyamine synthesis enzymes, detoxification enzymes, oxidation reduction enzymes, hydrolases, and proteases (6Robarie B. Hermo L. Knobil E. Neill J. The Physiology of Reproduction. Raven Press, New York1988: 999Google Scholar, 7Orgebin-Crist M.-C. (Bhasin S. Swevdloff R.S. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss, Inc., NY1996Google Scholar, 8Cornwall G. Hann S.R. J. Androl. 1995; 16: 379-383PubMed Google Scholar).The transcription factors that orchestrate androgen-dependent events in the testis and epididymis have not been identified, although the androgen receptor clearly plays a major role in such responses. Homeobox transcription factors are candidates to regulate spermatogenesis and sperm maturation, since they are known to regulate many other developmental events. The distinguishing feature of homeobox proteins is a conserved DNA-binding motif 60 amino acids in length, termed a homeodomain. The homeodomain is comprised of three α-helices; sequence specificity is conferred by key residues in the third helix that direct binding to base contacts in the major groove of DNA. The best understood homeobox proteins are those encoded by the hox/hom, prd/pax, and POU gene families (9Duboule D. Guidebook to the Homeobox Genes. Oxford University Press, Oxford1994Google Scholar). Studies in Drosophila melanogaster, Xenopus laevis, and mice have shown that members of these classical homeobox gene families are required for discrete events during development. For example, studies in null mutant mice have demonstrated that the Pax-6 gene activates a regulatory cascade necessary for eye development (10Gruss P. Walther C. Cell. 1992; 69: 719-722Abstract Full Text PDF PubMed Scopus (351) Google Scholar), the Oct-2 POU homeobox gene promotes late stages of B-cell maturation (11Corcoran L.M. Karvelas M. Nossal G.J.V. Ye Z.-S. Jacks T. Baltimore D. Genes Dev. 1993; 7: 570-582Crossref PubMed Scopus (238) Google Scholar), and Hox genes specify axial identity during embryogenesis (12Krumlauf R. Cell. 1994; 78: 191-201Abstract Full Text PDF PubMed Scopus (1730) Google Scholar).Homeobox transcription factor genes have been shown to be expressed in the male reproductive system, but none have been shown to be androgen-regulated. Many of these homeobox genes are expressed in germ cells of the testis. For example, the POU homeobox gene sperm-1 is expressed transiently prior to meiosis in germ cells (13Andersen B. Pearse II, R.V. Schlegel P.N. Cichon Z. Schonemann M.D. Bardin C.W. Rosenfeld M.G. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11084-11088Crossref PubMed Scopus (48) Google Scholar), and Hoxa-4 is expressed specifically in postmeiotic germ cells (14Wolgemuth D.J. Viviano C.M. Watrin F. Ann. N. Y. Acad. Sci. 1991; 637: 300-312Crossref PubMed Scopus (15) Google Scholar, 15Watrin F. Wolgemuth D.J. Dev. Biol. 1993; 156: 136-145Crossref PubMed Scopus (26) Google Scholar). Hoxb-4 is expressed by both germ cells and somatic cells in the testis, while Hoxd-4 is expressed by Leydig cells (15Watrin F. Wolgemuth D.J. Dev. Biol. 1993; 156: 136-145Crossref PubMed Scopus (26) Google Scholar). Both Hoxb-4 and Hoxd-4 are expressed by other adult organs besides testis (16Featherstone M.S. Baron A. Gaunt S. Mattei M.G. Duboule D. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 4760-4764Crossref PubMed Scopus (120) Google Scholar, 17Graham A. Papalopulu N. Lorimer J. McVey J.H. Tuddenham E.G.D. Krumlauf R. Genes Dev. 1988; 2: 1424-1438Crossref PubMed Scopus (111) Google Scholar). Little is known about the expression pattern of transcription factors in the epididymis. To our knowledge the only transcription factor genes identified as expressed in the epididymis are the homeobox gene Pax-2 (18Fickenscher H.R. Chalepakis G. Gruss P. DNA Cell Biol. 1993; 5: 381-391Crossref Scopus (54) Google Scholar) and the ETS-like transcription factor PEA3 (19Xin J.-H. Cowie A. Lachance P. Hassell J.A. Genes Dev. 1992; 6: 481-496Crossref PubMed Scopus (279) Google Scholar).In a search for developmentally regulated genes, we used the subtraction hybridization technique to isolate several cDNAs corresponding to novel genes (20MacLeod C.L. Fong A.M. Seal B.S. Walls L. Wilkinson M.F. Cell Growth & Differ. 1990; 1: 271-279PubMed Google Scholar), including the homeobox gene, Pem (21Wilkinson M.F. Kleeman J. Richards J. MacLeod C.L. Dev. Biol. 1990; 141: 451-455Crossref PubMed Scopus (61) Google Scholar, 22Sasaki A.W. Doskow J. MacLeod C.L. Rogers M.B. Gudas L.J. Wilkinson M.F. Mech. Dev. 1991; 34: 155-164Crossref PubMed Scopus (38) Google Scholar). The Pem homeodomain shares modest sequence identity with prd/pax homeodomains (22Sasaki A.W. Doskow J. MacLeod C.L. Rogers M.B. Gudas L.J. Wilkinson M.F. Mech. Dev. 1991; 34: 155-164Crossref PubMed Scopus (38) Google Scholar, 23Rayle R.E. Dev. Biol. 1991; 146: 255-257Crossref PubMed Scopus (19) Google Scholar), but its primary amino acid sequence is sufficiently unique to warrant classification in a different subfamily. The Pem gene is expressed in a unique pattern during embryogenesis. Tissues that contribute to the extraembryonic compartment express mouse Pem; the gene remains highly expressed in the placenta and yolk sac until term (21Wilkinson M.F. Kleeman J. Richards J. MacLeod C.L. Dev. Biol. 1990; 141: 451-455Crossref PubMed Scopus (61) Google Scholar, 24Lin T.-P. Labosky P.A. Grabel L.B. Kozak C.A. Pitman J.L. Kleeman J. MacLeod C.L. Dev. Biol. 1994; 166: 170-179Crossref PubMed Scopus (98) Google Scholar). The in vivo expression pattern of Pem in endodermal tissue is mimicked in pluripotent stem cell lines that differentiate in vitro; F9 embryonal carcinoma stem cells induced to differentiate into either the visceral or endodermal lineage up-regulate Pem mRNA expression (22Sasaki A.W. Doskow J. MacLeod C.L. Rogers M.B. Gudas L.J. Wilkinson M.F. Mech. Dev. 1991; 34: 155-164Crossref PubMed Scopus (38) Google Scholar) and accumulate Pem protein specifically in the outer layer of cells that possess characteristics of extraembryonic endoderm (24Lin T.-P. Labosky P.A. Grabel L.B. Kozak C.A. Pitman J.L. Kleeman J. MacLeod C.L. Dev. Biol. 1994; 166: 170-179Crossref PubMed Scopus (98) Google Scholar, 25Labosky P.A. Weir M.P. Grabel L.B. Dev. Biol. 1993; 159: 232-244Crossref PubMed Scopus (10) Google Scholar). Pem gene expression is also dramatically up-regulated in normal diploid embryonic stem cells induced to differentiate in vitro (22Sasaki A.W. Doskow J. MacLeod C.L. Rogers M.B. Gudas L.J. Wilkinson M.F. Mech. Dev. 1991; 34: 155-164Crossref PubMed Scopus (38) Google Scholar), although it is not known which specific differentiated cell types activate Pem gene expression.In this communication, we report that Pem gene expression is not restricted to embryogenesis. We show that in prepubertal and adult rats, the Pem gene is specifically transcribed in both male and female reproductive tissue and to a lesser extent in skeletal muscle. Transcript analyses revealed that Pem transcripts are derived from two promoters and undergo complex alternative splicing events that are regulated in a tissue-specific manner. The alternative splicing events alter both the 5′-UT 1The abbreviations used are: UTuntranslatedPddistal promoterPpproximal promoterPCRpolymerase chain reactionRT-PCRreverse transcriptase-PCR5′ RACE5′ rapid amplification of cDNA endsntnucleotide(s)TricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycinePIPES1,4-piperazinediethanesulfonic acidDHTdihydrotestosterone. and coding regions of Pem mRNA. We demonstrate androgen-dependent expression of Pem transcripts from the promoter used exclusively by male reproductive tissue. The complex and androgen-dependent pattern of Pem expression by alternative promoter usage and alternative splicing has important implications for the possible role of the Pem homeobox gene in development.DISCUSSIONIn this report, we characterized the genomic structure of the Pem gene, defined two promoters used in a tissue-specific manner, and demonstrated that Pem transcripts undergo alternative RNA splicing events. We showed that an androgen-dependent promoter, Pp, is used exclusively in male reproductive tissue, while the other promoter, Pd, is expressed in female reproductive tissue and at low levels in skeletal muscle (Fig. 2). We found that several different modes of splicing regulation are exerted on Pem transcripts: 1) alternative exon inclusion; 2) alternative exon skipping; and 3) alternative splice acceptor usage (Fig. 2).We showed that mRNAs transcribed from the Pp (T-transcripts) require androgens for expression (Fig. 4), which is likely to explain why the Pp promoter is active in testis and epididymis, and is not used detectably in placenta, muscle, or ovary. The temporal pattern of T-transcript expression during development differed in testis and epididymis. In prepubertal animals, T-transcript levels were very high in epididymis but low in testis. T-transcript levels were high as early as day 23 post partum in epididymis, while in testis T-transcripts remained barely detectable until day 44 and only reached levels similar to that of Pd-derived transcripts at later developmental times (Fig. 5). The explanation for why T-transcripts are regulated differently in testis and epididymis is not known. Since we showed that T-transcript expression in epididymis requires testosterone, it is likely that the early postnatal expression of this transcript in epididymis is due to the known presence of androgens in the lumen of the epididymis at this developmental time point (37Tindall D.J. Vitale R. Means A.R. Endocrinology. 1975; 97: 636-648Crossref PubMed Scopus (106) Google Scholar, 38Charest N.J. Petrusz P. Ordronneau P. Joseph D.R. Wilson E.M. French F.S. Endocrinology. 1989; 125: 942-947Crossref PubMed Scopus (38) Google Scholar). Less clear is why T-transcript levels are so low in testis. Expression of T-transcripts in the testis in vivo requires testosterone, based on experiments in EDS-treated rats, 2S. Maiti, M. Griswold, and M. F. Wilkinson, unpublished observations. but the available androgens in the testis may be insufficient to trigger strong expression. Androgen-binding protein, which is secreted by Sertoli cells and considered to act as an “androgen sink” in the testis and as an androgen-carrier protein to the epididymis, is known to be expressed at very high levels in rats (50-100-fold higher than in mice; 39Wang Y.-M. Sullivan P.M. Petrusz P. Yarbrough W. Joseph D.R. Mol. Cell. Endocrinol. 1989; 63: 85-92Crossref PubMed Scopus (45) Google Scholar) and thus may depress Pp transcription in rat testis. The specific androgens that are present in the testis at different developmental time points may also influence Pem expression. For example, the decline in the intratesticular levels of 5α-reductase after day 40 (40Preslock J.P. Endocrinol. Rev. 1980; 1: 132-139Crossref PubMed Scopus (24) Google Scholar) would cause a switch in the ratio of dihydrotestosterone to testosterone and thus may influence transcription from the Pp.The Pem gene is unusual in that it contains two promoter regions and three 5′-UT exons upstream of the coding region. As a result of alternative promoter usage and alternative splicing of these 5′-UT exons, Pem transcripts possess at least five different 5′ termini (the number of variants is even greater if one considers the multiple transcriptional initiation sites within both the Pp and the Pd). Since the use of some of these different 5′-UT sequences is regulated in a tissue- or androgen-dependent manner, it is tempting to speculate that they function in a regulatory capacity. We tested the effect of different Pem 5′-UT termini on translatability in vitro (Fig. 9) and found that Pem transcripts from the Pp (T-transcripts) were translated less efficiently than transcripts from the Pd (A-transcripts). Perhaps the male reproductive cell types that express Pp-derived transcripts down-regulate the level of Pem protein that is translated because deleterious effects would be caused by Pem protein overexpression. In skeletal muscle, a unique 5′-UT exon (the M exon) is included in Pem transcripts that is excluded in all other tissues (Fig. 7). We found that inclusion of the M exon depressed translation somewhat (Fig. 9), but since the effect was not dramatic, the M exon may regulate events other than translation. For example, it is known that 5′-UT sequences can regulate mRNA stability (45Peltz S.W. Brewer G. Bernstein P. Hart P.A. Ross J. Crit. Rev. Eukaryotic Gene Expr. 1991; 1: 99-126PubMed Google Scholar). It will be of interest to determine if the M exon plays a role in the dramatic induction of Pem transcripts in 10T1/2 mesenchymal stem cells when they commit to the muscle cell lineage (22Sasaki A.W. Doskow J. MacLeod C.L. Rogers M.B. Gudas L.J. Wilkinson M.F. Mech. Dev. 1991; 34: 155-164Crossref PubMed Scopus (38) Google Scholar). Secondary structure analysis by computer suggested that the different 5′ termini present in A-, M-, and T-transcripts possess different secondary structures that may be responsible for the different rates of translation. 3J. Doskow and M. F. Wilkinson, unpublished observations. Tissue-specific factors may be present in vivo that differentially bind to these secondary structure regions and thereby regulate the translation rate of Pem mRNAs that possess these different 5′ termini. Although many studies have demonstrated that translation is highly regulated in germ cells (46Schäfer M. Nayernia K. Engel W. Schäfer U. Dev. Biol. 1995; 172: 344-352Crossref PubMed Scopus (116) Google Scholar, 47Hecht N.B. Dev. Genet. 1995; 16: 95-103Crossref PubMed Scopus (113) Google Scholar), little is known about translational regulation in somatic cells of the testis and epididymis, where Pem transcripts are expressed. 4J. S. Lindsey and M. F. Wilkinson, submitted for publication. We identified an alternatively spliced transcript (ΔE4) that encodes a novel form of the Pem protein (Pem-E). Many transcription factors, including homeobox transcription factors, are known to be expressed as multiple isoforms as a result of tissue-specific alternative RNA splicing (41López A.J. Dev. Biol. 1995; 172: 396-411Crossref PubMed Scopus (87) Google Scholar). Pem-E shares the amino terminus with the classical Pem protein but lacks the homeodomain and thus may not bind DNA. Since the amino-terminal region of Pem is, by far, the most conserved region of this protein based on comparison of the primary amino acid sequence of mouse and rat Pem (35Maiti S. Doskow J. Sutton K. Nhim R.P. Lawlor D.A. Levan K. Lindsey J.S. Wilkinson M.F. Genomics. 1996; (in press)PubMed Google Scholar), this region may possess functional attributes. For example, the amino-terminal region may serve as a binding interface that permits Pem and Pem-E to bind other proteins. Many homeobox proteins have been shown to use amino acids outside of the homeodomain to interact with other transcription factors, including other homeobox proteins (9Duboule D. Guidebook to the Homeobox Genes. Oxford University Press, Oxford1994Google Scholar, 42Vershon A.K. Jin Y. Johnson A.D. Genes Dev. 1995; 9: 182-192Crossref PubMed Scopus (58) Google Scholar, 43Kämper J. Reichmann M. Romeis T. Bölker M. Kahmann R. Cell. 1995; 81: 73-83Abstract Full Text PDF PubMed Scopus (200) Google Scholar). The importance of regions outside of the homeodomain for biological function is underscored by a recent study showing that a mutant Ftz protein completely lacking the homeodomain correctly regulates downstream target genes in vivo, probably because it is still able to bind to other transcription factors (44Copeland J.W.R. Nasiadka A. Dietrich B.H. Krause H.M. Nature. 1996; 379: 162-164Crossref PubMed Scopus (83) Google Scholar). Pem-E may act as an inhibitor protein that competes with classical Pem for interaction with another transcription factor, but by virtue of its inability to bind to DNA, it would exert a dominant negative effect. By analogy, the Id inhibitor protein possesses a helix-loop-helix motif and thus can dimerize with other helix-loop-helix proteins, such as myoD, but because Id lacks a DNA-binding domain it prevents these interacting helix-loop-helix proteins from activating the transcription of downstream target genes (41López A.J. Dev. Biol. 1995; 172: 396-411Crossref PubMed Scopus (87) Google Scholar).Most known examples of alternative transcriptional and posttranscriptional events in male reproductive tissue are known to occur in the germ cells (47Hecht N.B. Dev. Genet. 1995; 16: 95-103Crossref PubMed Scopus (113) Google Scholar). For example, the c-mos, c-abl, pim-1, cytochrome c, cyclin D3, superoxide dismutase, hoxa-4, proopiomelanocortin, and SRY genes use alternative promoters in germ cells of the testis that differ from the promoters used in somatic cells (48Sorrentino V. McKinney M.D. Giorgi M. Geremia R. Fleissner E. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 2191-2195Crossref PubMed Scopus (82) Google Scholar, 49Ito E. Toki T. Ishihara H. Ohtani H. Gu L. Yokoyama M. Engel J.D. Yamamoto M. Nature. 1993; 362: 466-468Crossref PubMed Scopus (257) Google Scholar, 50Hake L.E. Hecht N.B. J. Biol. Chem. 1993; 268: 4788-4797Abstract Full Text PDF PubMed Google Scholar, 51Yiu G.Y. Gu W. Hecht N.B. Nucleic Acids Res. 1994; 22: 4599-4606Crossref PubMed Scopus (24) Google Scholar, 52Gu W. Morales C. Hecht N.B. J. Biol. Chem. 1995; 270: 236-243Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 53Ravnik S.E. Rhee K. Wolgemuth D.J. Dev. Genet. 1995; 16: 171-178Crossref PubMed Scopus (49) Google Scholar, 54Hacker A. Capel B. Goodfellow P. Lovell-Badge R. Development. 1995; 121: 1603-1614Crossref PubMed Google Scholar, 55Propst F. Rosenberg M.P. Vande Woude G.F. Trends Genet. 1988; 4: 183-187Abstract Full Text PDF PubMed Scopus (72) Google Scholar). One hypothesis to explain the common usage of alternative promoters in germ cells is that it results from the changes in the chromatin structure needed to produce spermatozoa. This restructuring would not occur in somatic cells of the testis and epididymis, and thus transcriptional regulation unique to these tissues is not necessarily expected. The Pem gene is expressed by somatic cells of the testis and epididymis,4 and thus it will be of interest to determine how and why it is regulated in such a complex manner at both the transcriptional and post-transcriptional level.Since the Pem gene encodes a homeodomain-containing protein, it is reasonable to suppose that the Pem protein is a transcription factor that regulates specific events during male gametogenesis. The finding that the Pem gene depends on androgen for expression in the epididymis suggests that, in turn, Pem may regulate androgen-dependent events in the epididymis. To our knowledge no transcription factors have previously been shown to be androgen-regulated in the epididymis. The homeobox transcription factor, Pax-2, is clearly regulated by a distinct mechanism, since it is expressed in the epididymis of tfm mice, which lack androgen receptors (18Fickenscher H.R. Chalepakis G. Gruss P. DNA Cell Biol. 1993; 5: 381-391Crossref Scopus (54) Google Scholar). Several candidate downstream genes are known to require androgens for expression in the epididymis (directly or indirectly) and thus may be regulated by Pem, including those encoding 5α-reductase, carboxypeptidase metalloprotein D/E (AEG, CRISP-1), the retinol binding protein B/C (ESPI), the glutathione peroxidase-like protein GPX, the glutamyltranspeptidase GGT, nerve growth factor, and E-cadherin (7Orgebin-Crist M.-C. (Bhasin S. Swevdloff R.S. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss, Inc., NY1996Google Scholar, 8Cornwall G. Hann S.R. J. Androl. 1995; 16: 379-383PubMed Google Scholar). The epididymis has multiple functions, many of which depend on the presence of androgens and thus may be regulated by Pem: (i) induction of spermatozoa motility capability, (ii) spermatozoa membrane alterations that permit fertilization competence, (iii) changes in the methylation status of spermatozoa genes, and (iv) spermatozoa storage (6Robarie B. Hermo L. Knobil E. Neill J. The Physiology of Reproduction. Raven Press, New York1988: 999Google Scholar, 7Orgebin-Crist M.-C. (Bhasin S. Swevdloff R.S. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss, Inc., NY1996Google Scholar, 8Cornwall G. Hann S.R. J. Androl. 1995; 16: 379-383PubMed Google Scholar, 56Ariel M. Cedar H. McCarrey J. Nat. Genet. 1994; 7: 59-63Crossref PubMed Scopus (142) Google Scholar). Since the Pem gene is specifically expressed in the distal corpus/proximal cauda portion of the epididymis,4 the site where spermatozoa gain motility capability and membrane alterations necessary for fertilization competence (57Blaquier J.A. Cameo M.S. Cuasnicu P.S. Gonzalez Echeverria M.F. Piñeiro L. Tezon J.G. Ann. N. Y. Acad. Sci. 1988; 541: 292-296Crossref PubMed Scopus (20) Google Scholar, 58Moore H.D.M. Hartman T.D. Smith C.A. J. Reprod. Fertil. 1986; 78: 327-336Crossref PubMed Scopus (30) Google Scholar), it will be of interest to determine whether Pem regulates these final maturation events. INTRODUCTIONAndrogens are of paramount importance to spermatogenesis in the testis and sperm maturation in the epididymis. Testosterone alone maintains spermatogenesis in gonadotropin-deficient animals, including hypophysectomized rats and mutant hypogonadal mice (1Santulli R. Sprando R.L. Awoniyi C.A. Ewing L.L. Zirken B.R. Endocrinology. 1990; 126: 95-101Crossref PubMed Scopus (52) Google Scholar, 2Sun Y. Wreford N.G. Robertson D.M. de Kretser D.M. Endocrinology. 1990; 127: 1215-1223Crossref PubMed Scopus (98) Google Scholar, 3Singh J. O'Neill C. Handelsman D.J. Endocrinology. 1995; 136: 5311-5321Crossref PubMed Google Scholar). Evidence suggests that testosterone drives spermatogenesis by acting on Sertoli cells and peritubular cells, both of which express androgen receptors (4Sar M. Hall S.H. Wilson E.M. French F.S. Russell L.D. Griswold M.D. The Sertoli Cell. Cache River Press, Clearwater, FL1993: 510Google Scholar, 5Norton J.N. Skinner M.K. Endocrinology. 1989; 124: 2711-2719Crossref PubMed Scopus (60) Google Scholar). Sertoli cells perform numerous functions critical for spermatogenesis by virtue of their intimate contact with differentiating germ cells within the seminiferous tubule. Androgens have been known to be critical for epididymal function since early in this century. They regulate the proliferation and differentiation of somatic cells in the epididymis and control the microenvironment of the maturing spermatozoa by regulating the synthesis of adhesion proteins in the epididymis, the secretion of proteins into the luminal fluid that are in contact with the spermatozoa, and the transport of ions and small organic molecules across the epididymal epithelium (6Robarie B. Hermo L. Knobil E. Neill J. The Physiology of Reproduction. Raven Press, New York1988: 999Google Scholar, 7Orgebin-Crist M.-C. (Bhasin S. Swevdloff R.S. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss, Inc., NY1996Google Scholar). Secreted proteins under androgen control in the epididymis include steroid-metabolizing enzymes, polyamine synthesis enzymes, detoxification enzymes, oxidation reduction enzymes, hydrolases, and proteases (6Robarie B. Hermo L. Knobil E. Neill J. The Physiology of Reproduction. Raven Press, New York1988: 999Google Scholar, 7Orgebin-Crist M.-C. (Bhasin S. Swevdloff R.S. Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss, Inc., NY1996Google Scholar, 8Cornwall G. Hann S.R. J. Androl. 1995; 16: 379-383PubMed Google Scholar).The transcription factors that orchestrate androgen-dependent events in the testis and epididymis have not been identified, although the androgen receptor clearly plays a major role in such responses. Homeobox transcription factors are candidates to regulate spermatogenesis and sperm maturation, since they are known to regulate many other developmental events. The distinguishing feature of homeobox proteins is a conserved DNA-binding motif 60 amino acids in length, termed a homeodomain. The homeodomain is comprised of three α-helices; sequence specificity is conferred by key residues in the third helix that direct binding to base contacts in the major groove of DNA. The best understood homeobox proteins are those encoded by the hox/hom, prd/pax, and POU gene families (9Duboule D. Guidebook to the Homeobox Genes. Oxford University Press, Oxford1994Google Scholar). Studies in Drosophila melanogaster, Xenopus laevis, and mice have shown that members of these classical homeobox gene families are required for discrete events during development. For example, studies in null mutant mice have demonstrated that the Pax-6 gene activates a regulatory cascade necessary for eye development (10Gruss P. Walther C. Cell. 1992; 69: 719-722Abstract Full Text PDF" @default.
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• W2022787977 title "The Homeobox Gene" @default.
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