Restricted innervation of uterus and placenta during pregnancy: Evidence for a role of the repelling signal Semaphorin 3A

Because data from the literature suggest a lack of innervation of the placenta, we have investigated placenta, umbilical cord, and uterus to identify the molecules that play a role in regulating innervation in these organs. Neuropilin-1 and Plexin-A1 are cell surface proteins that form a receptor complex for Semaphorin 3A (Sema 3A), a secreted molecule mediating repelling signals for axonal growth cones. We have analyzed the expression of Neuropilin-1, Plexin-A1, and Semaphorin 3A in the above-mentioned tissues on the hypothesis that these molecules could regulate innervation in these organs during gestation. We found that nervous fibers are only present in the proximal part of the umbilical cord, close to the newborn, and in nongestational uterine tissues. In contrast, nervous fibers are not present in the distal segment of the umbilical cord, in the placenta and in the uterine tissues during gestation. We also found that Sema 3A receptors, Neuropilin-1 and Plexin-A1, are expressed by the nervous fibers of the proximal part of the umbilical cord, whereas Sema 3A is secreted in the umbilical cord, in the placenta, and in gestational uterine tissues. We report that a factor secreted in the umbilical cord induces the collapse of neurite growth cones in vitro and provide evidence that this factor is Sema 3A. In summary, our results suggest that the chemorepulsive signals mediated by Sema 3A play an important role in preventing nerve fibers growth in the umbilical cord and in gestational uterine tissues. The inhibition of nerve growth into the myometrium as well as into the placenta could be considered fundamental processes to preserve the fetus from external stressful events.