Quantitative assessment of the stage of neuronal maturation in the developing human fetal gut—A new dimension in the pathogenesis of developmental anomalies of the myenteric plexus

Abstract

There are two main theories of the normal development of the enteric nervous system: the classical theory suggests that the enteric neuroblasts migrate along the alimentary tract in a single cranio-caudal direction. However, the second theory postulates a dual gradient of neuronal development. The present study aims to support the second theory and contribute to the understanding of the pathogenesis of Hirschsprung's disease and its allied gut motility disorders. Using a histomorphometric method, quantitative estimation of the myenteric intraganglionic neuronal development was made in tissues from various selected levels of the gut in 32 normal human fetuses of 11 to 24 weeks ovulation age. A parallel study with special chromatin staining was carried out from these materials to investigate different neurons in the myenteric plexus. Development of intraganglionic neurons was shown to be more advanced in the esophagus, less so in the rectosigmoid and least so in the ileocecal region: the mean values of neuronal and nuclear volume were found in the esophagus greater than in rectosigmoid and ileocecal region as ovulation age progressed. Intraganglionic mitotic figures were detected at all the selected levels of the gut. A decrease of the mitosis index as age progressed was observed. We showed that myenteric neurons followed a dual gradient of development proceeding from both ends to the middle of the gut in mid-trimester human fetuses. Our findings are compatible with the suggestion that any alterations in the fetal gut microenvironment may affect seriously the normal development of a multipotential precursor cell population resulting in various congenital anomalies of the myenteric plexus.