Alternative splicing: an important mechanism for myometrial gene regulation that can be manipulated to target specific genes associated with preterm labour
© Tyson-Capper; licensee BioMed Central Ltd. 2007
Published: 1 June 2007
Considerable effort has been expended in attempting to distinguish genes that contribute to initiating the onset of term and preterm labour (PTL) from those that change in expression as a consequence of the progression of labour. The ability to define more clearly the genes involved in triggering labour contractions should lead to the development of new effective and safer strategies to prevent preterm birth. There is ample evidence to suggest that specific genes are co-ordinately regulated within the upper and lower regions of the myometrium prior to and during parturition and many of these genes are regulated by alternative pre-mRNA splicing. This mini-review highlights that expression of a range of different splicing factors, with defined roles in pre-mRNA splicing, is both temporally and spatially regulated within the uterine smooth muscle during pregnancy and labour. Moreover, several of these splicing factors play key roles in controlling the differential expression of specific regulatory proteins involved in uterine signalling and uterine quiescence. In addition, antisense morpholino oligonucleotide manipulation of pre-mRNA splicing may have potential in defining and targeting uterine pro-labour genes and thus contribute to the development of new therapeutic approaches to prevent PTL.
Splicing factors and myometrial genes
Antisense oligonucleotides as modulators of myometrial alternative splicing
To summarise, alternative splicing plays an important role in modulating myometrial gene regulation during pregnancy and labour by naturally increasing the coding capacity of myometrial mRNA transcripts to generate different protein isoforms with enhanced activity and also isoforms with markedly different activities. This mini-review proposes that alternative splicing within the myometrium during pregnancy, term and preterm labour is not likely to be a static process but subject to change. The expression profiles for splicing factors change dramatically within the myometrium in pregnancy; these factors have been shown to have substrate-specific roles in alternative splicing and it is possible that they may modulate the expression of many more alternately spliced myometrial proteins involved in myometrial quiescence and contractility. Therefore, a more complete analysis of alternative splicing events coupled with transcriptional control of myometrial genes would be advantageous to increase our understanding of the complex co-ordinated molecular processes that regulate myometrial genes in pregnancy and labour. Finally, the use of highly specific antisense morpholino oligonucleotides may prove to be a valuable technique to identify and 'switch off' specific genes the activation of which is linked with the initiation of term and preterm labour.
The author wishes to acknowledge Professor GN Europe-Finner, Professor SC Robson (Newcastle University, UK) and Dr Jon Moulton (GeneTools, LLC). Ferring, Perkin Elmer and Serono supported publication costs. The author also wishes to acknowledge support from the Special Non-invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence (LSHB-CT-2004-503243) PTL workshops.
This article has been published as part of BMC Pregnancy and Childbirth Volume 7, Supplement 1, 2007: Proceedings of the First and Second European Workshops on Preterm Labour of the Special Non-Invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2393/7?issue=S1.
- Nadal-Ginard B, Smith CW, Patton JG, Breitbart RE: Alternative splicing is an efficient mechanism for the generation of protein diversity: contractile protein genes as a model system. Adv Enzyme Regul. 1991, 31: 261-86. Review.View ArticlePubMedGoogle Scholar
- Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW: A novel spliced variants of the type 1 corticoid-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes. Mol Endocrinol. 1999, 13: 2189-2202. 10.1210/me.13.12.2189.View ArticlePubMedGoogle Scholar
- Havelock JC, Keller P, Muleba N, Mayhew BA, Casey BM, Rainey WE, Ann Word RA: Human Myometrial Gene Expression Before and During Parturition. Biol Reprod. 2005, 72: 707-719. 10.1095/biolreprod.104.032979.View ArticlePubMedGoogle Scholar
- Europe-Finner GN, Phaneuf S, Watson SP, López Bernal A: Identification and expression of G-proteins in human myometrium : up-regulation of Gαs in pregnancy. Endocrinology. 1993, 132: 2484-2490. 10.1210/en.132.6.2484.PubMedGoogle Scholar
- Brodt-Eppley J, Myatt L: Prostaglandin receptors in lower segment myometrium during gestation and labor. Obstet Gynecol. 1999, 93 (1): 89-93. 10.1016/S0029-7844(98)00378-0.View ArticlePubMedGoogle Scholar
- Matlin AJ, Clark F, Smith CWJ: Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol. 2005, 6: 386-398. 10.1038/nrm1645.View ArticlePubMedGoogle Scholar
- Pollard AJ, Sparey C, Krainer AR, Robson SC, Europe-Finner GN: Spatio-temporal expression of the trans-acting splicing factors SF2/ASF and hnRNPA1/A1B in the myometrium of the pregnant human uterus: a molecular mechanism for regulating regional isoform expression in vivo. J Clin Endocrinol Metab. 2000, 85: 1928-1936. 10.1210/jc.85.5.1928.PubMedGoogle Scholar
- Mayeda A, Krainer AR: Modulation of exon skipping and inclusion by heterogenous nuclear ribonuclearprotein A1 and pre-mRNA splicing factor SF2/ASF. Cell. 1993, 68: 365-375. 10.1016/0092-8674(92)90477-T.View ArticleGoogle Scholar
- Pollard AJ, Krainer AR, Robson SC, Europe-Finner GN: Alternative splicing of the adenylyl cyclase stimulatory G-protein Gαs is regulated by SF2/ASF and hnRNP A1 in vivo and involves the use of an unusual 3' TG acceptor splice site. J Biol Chem. 2002, 277: 15241-15251. 10.1074/jbc.M109046200.View ArticlePubMedGoogle Scholar
- Europe-Finner GN, Phaneuf S, Tolkovsky AM, Watson SP, López Bernal A: Down-regulation of G alpha s in human myometrium in term and preterm labor: a mechanism for parturition. J Clin Endocrinol Metab. 1994, 79 (6): 1835-9. 10.1210/jc.79.6.1835.PubMedGoogle Scholar
- Price SA, López Bernal A: Uterine Quiescence:The role of cyclic AMP. Exp Physiol. 2001, 86.2: 265-272. 10.1113/eph8602182.View ArticleGoogle Scholar
- Price SA, Pochun I, Phaneuf S, López Bernal A: Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium. J Endocrinol. 2000, 164: 21-30. 10.1677/joe.0.1640021.View ArticlePubMedGoogle Scholar
- Bailey J, Philips R, Pollard AJ, Gilmore K, Robson SC, Europe-Finner GN: Characterisation and functional analysis of CREM and ATF2 isoforms in the human myometrium during fetal maturation: identification of a novel ATF2 species with potent trans-activation properties. J Clin Endocrinol Metab. 2002, 87 (4): 1717-28. 10.1210/jc.87.4.1717.View ArticlePubMedGoogle Scholar
- Tyson-Capper AJ, Bailey J, Krainer AR, Robson SC, Europe-Finner GN: The switch in alternative splicing of cyclic AMP response element modulator protein CREMτ2α (activator) to CREMα (repressor) in human myometrial cells is mediated by srp40. J Biol Chem. 2005, 280 (41): 34521-9. 10.1074/jbc.M505344200.View ArticlePubMedGoogle Scholar
- Sazani P, Vacek MM, Kole R: Short-term and long-term modulation of gene expression by antisense therapeutics. Curr Opin Biotechnol. 2002, 13: 468-472. 10.1016/S0958-1669(02)00366-X.View ArticlePubMedGoogle Scholar
- Sazani P, Kole R: Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. J Clin Invest. 112: 481-486. 10.1172/JCI200319547.Google Scholar
- Mann CJ, Honeyman K, Cheng AJ: Antisense-induced exon skipping and synthesis of the dystrophin gene in the mdx mouse. Proc Natl Acad Sci USA. 2001, 98: 42-46. 10.1073/pnas.011408598.PubMed CentralView ArticlePubMedGoogle Scholar
- Tyson-Capper AJ, Europe-Finner GN: Novel targeting Of COX-2 pre-mRNA using antisense morpholino oligonucleotides: Suppression of COX-2 activity in human amnion-derived WISH and myometrial cells. Mol Pharmacol. 2006, 69: 796-804.PubMedGoogle Scholar
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