Neural tube closure in humans initiates at multiple sites: evidence from human embryos and implications for the pathogenesis of neural tube defects

The closure of the neural tube (NT) in the human embryo has generally been described as a continuous process that begins at the level of the future ce rvical region and proceeds both rostrally and caudally. On the other hand, multiple initiation sites of NT closure have been demonstrated in mice and other animals. In humans, based on the study of neural tube defects (NTD) i n clinical cases, van Alien et al. (1993) proposed a multisite NT closure m odel in which five closure sites exist in the NT of human embryos. In the p resent study, we examined human embryos in which the NT was closing (Congen ital Anomaly Research Center, Kyoto University) grossly and histologically, and found that NT closure in human embyos initiates at multiple sites but that the mode of NT closure in humans is different from that in many other animal species. In addition to the future cervical region that is widely ac cepted as an initiation site of NT closure (Site A), the mesencephalic-rhom bencephalic boundary was found to be another initiation site (Site B). The second closure initiating at Site B proceeds bidirectionally and its caudal extension meets the first closure from Site A over the rhombencephalon, an d the rostral extension of the second closure meets another closure extendi ng from the rostral end of the neural groove (Site C) over the prosencephal on, where the anterior neuropore closes. The caudal extension of the first closure initiating at Site A was found to proceed all the way down to the c audal end of the neural groove where the posterior neuropore is formed, ind icating that in humans, NT closure does not initiate at the caudal end of t he neural groove to proceed rostrally. Since there is a considerable specie s difference in the mode of NT closure, we should be careful when extrapola ting the data from other animals to the human. It seems that the type of NT D affects the intrauterine survival of abnormal embryos. Almost all the emb ryos with total dysraphism appear to die by 5 weeks of gestation, those wit h an opening over the rhombencephalon by 6.5 weeks, and those with a defect at the frontal and parietal regions survive beyond 7 weeks.