TRANSCRIPTIONAL REGULATION OF CERVICAL COMPETENCE DURING PREGNANCY

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Much of the difficulty in preventing preterm birth resides in the fact that we do not understand what controls the timing of parturition in women. Until recently, the cervix has been credited with little more than a passive role, remaining closed during pregnancy only to exponentially increase its diameter to 10 cm or more during labor. It is now clear, however, that shortening of the cervix in the second trimester is an early predictor of preterm birth, suggesting that cervical changes occur several weeks prior to uterine contractions of preterm labor. Thus, an understanding of the cellular and molecular mechanisms that regulate progressive changes in cervical function are needed to impact the preterm birth rate. As part of our overall goal to understand the transcriptional regulation of cervical function during pregnancy, the transcription factor microphthalmia-associated transcription factor (MITF) was identified as a differentially-regulated gene in cervical tissues from women at term with an unripe cervix and women at term with cervical dilation and effacement. In subsequent experiments, we defined a novel isoform of MITF in the female reproductive tract and found dramatic decreases in this isoform in cervical tissues from women in labor. These results, together with the striking parturition phenotype of mice homozygous for mutations in MITF, provide the foundation for the current hypothesis, namely that MITF is an important transcriptional regulator of cervical competence during pregnancy. To test this hypothesis, we propose: (1) To determine tissue- and isoform-specific expression of MITF in cervix and myometrium during pregnancy and the postpartum time period, (2) to identify target genes of MITF regulation in cervical stromal cells, and (3) to identify regulators of MITF gene expression in stromal and smooth muscle cells of the uterus and cervix. Human cervical tissues and cells in culture will be utilized to define the cellular targets of MITF and its regulation. Wild type and mutant mi/mi mice will be used to study the physiologic role of this factor during pregnancy. Finally, the impact of progesterone receptor- and cytokine-induced signal transduction pathways on MITF gene expression and cervical function during pregnancy will be evaluated. The proposed studies will not only answer important questions regarding mechanisms in the initiation of cervical remodeling and labor, but will also provide insight into the physiologic regulation of cervical competence through the transcription factor MITF. It is anticipated that understanding these basic mechanisms and the gene targets of MITF will lead to the development of therapeutic strategies to prevent or abrogate cervical incompetence, preterm cervical ripening, and labor.