T. Nakatsu

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 cervical 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) in clinical cases, van Allen et al. (1993) proposed a multi-site NT closure model in which five closure sites exist in the NT of human embryos. In the present study, we examined human embryos in which the NT was closing (Congenital 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 accepted as an initiation site of NT closure (Site A), the mesencephalic-rhombencephalic 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, and the rostral extension of the second closure meets another closure extending from the rostral end of the neural groove (Site C) over the prosencephalon, 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 caudal end of the neural groove where the posterior neuropore is formed, indicating that in humans, NT closure does not initiate at the caudal end of the neural groove to proceed rostrally. Since there is a considerable species difference in the mode of NT closure, we should be careful when extrapolating the data from other animals to the human. It seems that the type of NTD affects the intrauterine survival of abnormal embryos. Almost all the embryos with total dysraphism appear to die by 5 weeks of gestation, those with an opening over the rhombencephalon by 6.5 weeks, and those with a defect at the frontal and parietal regions survive beyond 7 weeks.

Embryonic hydromyelia: cystic dilatation of the lumbosacral neural tube in human embryos

Abstract. In a large collection of human embryos (the Kyoto Collection of Human Embryos, Kyoto University), we encountered five cases with abnormal dilatation of the neural tube at the lumbosacral level. In these examples, the central canal was enlarged, and the roof plate of the neural tube was extremely thin and expanded. The mesenchymal tissue was scarce or lacking between the roof plate and the surface ectoderm. This type of anomaly was assumed to be formed after neural tube closure and may be an early form of spina bifida. In two of the cases, some abnormal cells were found ectopically between the thin roof plate and the surface ectoderm. Morphologically, these cells resembled those forming spinal ganglia and could be of the neural crest origin. Since neural crest cells are pluripotent and can differentiate into a variety of tissues, such ectopic cells might undergo abnormal differentiation into teratomatous tumors and/or lipomas, which are frequently associated with spina bifida. We also discuss the definition of spina bifida and the classification of neural tube defects from the embryological and pathogenic viewpoints and propose a new classification of neural tube defects.

Construction and application of 3D model sequence to illustrate the development of the human embryo

Embryology is one of the basic subjects in medical education, to learn the process of human development especially from fertilization to birth. The shape deformation in the development of human embryo is one of the most important points to be comprehended, but it is difficult to illustrate the deformation by texts, 2D drawings, photographs and so on, because it is extremely complicated. The purpose of our research is to construct a 3D model sequence to illustrate the deformation of human embryo, and to make the model sequence into the teaching materials for medical education. Firstly, 3D images of the specimens of human embryo were acquired using MR microscopy. Next, an initial 3D model sequence was manually modified by comparing with the features of the acquired images under the supervision of medical doctors, because the images were influenced not only by the noise or limitation of resolution in MR image acquisition, but also by the variation of shape depending on the difference of subject. Using the constructed 3D model sequence, CG animations and an interactive VRML system were composed as the teaching materials for embryology. These materials were quite helpful to understand the shape deformation compared with the conventional materials.

Normal and abnormal neurulation in humans: Implications for the pathogenesis of neural tube defects

The closure of the neural tube (NT) in humans has generally been described as a continuous process that begins in the region of the future neck and proceeds both rostrally and caudally, Recently, four separate initiation sites for neural tube fusion have been demonstrated in mice and other experimental animals. In humans, based on the study of neural tube defects (NTD) in clinical cases, van Allen et al. proposed a multisite NT closure model which argued that five closure sites exist in the NT of human embryos.1 By direct observation of human embryos with the fusing NT (Congenital Anomaly Research Center, Kyoto University, Kyoto, Japan), it was revealed that NT closure in human embryos does initiate at multiple sites but that the mode of NT closure in humans may be different from that in rodent species. In addition to the future cervical region which is widely accepted as an initiation site of NT closure, the mesencephalic‐rhombencephalic border was found to be another initiation site. Because there may be such species difference in the mode of NT closure, we should be careful when extrapolating data from experimental animals as it may not apply to humans. It is likely that the type of NTD affects the intra‐uterine survival rate of human embryos with NTD. Almost all of the embryos with total dysraphism appear to die by 5 weeks of gestation. while those with an opening over the rhombencephalon appear to die by 6.5 weeks, and those with a defect at the frontal and parietal regions survive beyond 7 weeks.

Neurulation in the human embryo revisited

ABSTRACT It used to be widely accepted that neural tube closure in the human initiates at the level of the future neck and proceeds both cranially and caudally like zip fastener closing. This continuous closure model was recently challenged, and observation of human embryos at the neurulation stage revealed that the closure of the human neural tube initiates at multiple sites. Multi‐site closure of the neural tube has been observed in many other animal species, but the initiation sites and the process of neural tube closure are variable among species. Therefore we should be careful when extrapolating the data of normal and abnormal neurulation in laboratory animals to the human. Recent studies in mouse genetics and developmental biology have shown that neural tube defects are quite heterogeneous both etiologically and pathogenetically. Gene mutations responsible for human neural tube defects are largely unknown, but molecular studies of human cases of neural tube defects and their comparison with the mouse genome data should provide a molecular basis for human neural tube defects.

Visualization of Intracranial Structures in Early Human Embryos Using 3-D Computer Graphics Technique

In classic human embryology, one of the most important techniques to observe embryonic structures three‐dimensionally (3‐D) was to reconstruct embryos or their parts using wax plate models from serial histological sections. However, wax plate reconstruction does not allow observation of internal structures and lumens unless the models are cut after reconstruction. The development of computer graphics has enabled us to reconstruct various biologic structures on the viewing screen and to manipulate the computer images as freely as we desire. Nevertheless, until now computer reconstruction has not been used frequently to study human organogenesis. We reviewed and photographed serial histological sections of early human embryos, projected these photographed slides onto a screen and traced the outlines of specific structures under study on a digitizing pad that was interfaced with a 16 bit computer. The digitized images were combined using a software for 3‐D reconstruction. With this technique, we were able to visualize the anatomical localization and interrelation of various structures inside the human head during the embryonic period. The 3‐D reconstruction technique should be of potential use for the study of normal and abnormal morphogenesis.

Computer graphics to illustrate the development of a human embryo for professional medical education

This sketch describes three dimensional (3D) computer graphics (CG) produced to illustrate the development of a human embryo for education in embryology, which is one of the basic subjects in professional medical education (Fig. 1). Although similar CG have already been produced for TV programs, they are insufficient in precision for professional medical education.