One of the most prominent questions in biology today is the elucidation of the mechanisms that causes birth of the fetus. Remodeling of the cervix is a critical early indicator that heralds the final stages of labor. Innervation of the pregnant cervix is required for term vaginal birth. Evidence in humans and our work in the mouse have raised the possibility that innervation and immigration of leukocytes are two linked processes essential for ripening of the cervix. We recently reported a novel finding that the innervation of the murine cervix is significantly increased by the day before birth. These findings lead us to propose that increased innervation of the prepartum cervix is a critical process that triggers immigration of leukocytes. The immigration and activation of immune cells within the cervix results in the release of collagenase and elastase, a necessary process for softening and dilation of the cervix preparatory to a normal vaginal birth. At present, the origin, identity, and connectivity of the increased neural fibers in the late-term pregnant cervix are unknown. Although, several different neural regions have been described to project to the cervix, determination of which regions are responsible for the large increase in axons that occurs prior to term is not known and is one major goals of my laboratory. To solve this we are using approaches that: 1) will examine proteins and mRNA expression of genes involved in the growth of neural fibers in regions critical to cervical innervation, 2) use surgical transections to disrupt neural projections to the cervix to determine the role of individual nerves in the initiation of the birth process, and 3) combine these techniques with neural tract tracing methods to determine the role of neural innervation in recruitment and activation of leukocytes in the prepartum cervix. We propose that neural innervation of the late-term cervix is required for immune cell function and gene activities that "ripen" the cervix.

These specific aims will test crucial hypotheses of the role of neural innervation of the cervix in processes that culminate in cervical remodeling. Insights from these studies will lead to novel neural or immune approaches that predict diversities in timing of birth, arrest premature onset of labor, or treat situations where labor fails to progress.