de Bree K et al. (2018), The development of the human notochord.

XB-ART-55640

PLoS One 2018 Oct 04;1310:e0205752. doi: 10.1371/journal.pone.0205752.

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The development of the human notochord.

de Bree K , de Bakker BS , Oostra RJ .

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The notochord is a major regulator of embryonic patterning in vertebrates and abnormal notochordal development is associated with a variety of birth defects in man. Proper knowledge of the development of the human notochord, therefore, is important to understand the pathogenesis of these birth defects. Textbook descriptions vary significantly and seem to be derived from both human and animal data whereas the lack of references hampers verification of the presented data. Therefore, a verifiable and comprehensive description of the development of the human notochord is needed. Our analysis and three-dimensional (3D) reconstructions of 27 sectioned human embryos ranging from Carnegie Stage 8 to 15 (17-41 days of development), resulted in a comprehensive and verifiable new model of notochordal development. Subsequent to gastrulation, a transient group of cells briefly persists as the notochordal process which is incorporated into the endodermal roof of the gut while its dorsal side attaches to the developing neural tube. Then, the notochordal process embeds entirely into the endoderm, forming the epithelial notochordal plate, which remains intimately associated with the neural tube. Subsequently, the notochordal cells detach from the endoderm to form the definitive notochord, allowing the paired dorsal aortae to fuse between the notochord and the gut. We show that the formation of the notochordal process and plate proceeds in cranio-caudal direction. Moreover, in contrast to descriptions in the modern textbooks, we report that the formation of the definitive notochord in humans starts in the middle of the embryo, and proceeds in both cranial and caudal directions.

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Species referenced: Xenopus
Genes referenced: fubp1 nos1

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	Fig 1. Human notochord development textbook concepts compared to our proposed theory.Schematic summary of the two main developmental concepts in modern textbooks. Ventral view with removed endoderm. The black lines indicate the level of the transversal sections (epiblast/ectoderm is superior in each section). In A the notochord develops in two phases. First the notochordal process (NP) extends over almost the entire length of the embryo (left). Within the notochordal process is a luminal extension of the primitive pit. The NP intercalates between the endoderm and the bottom of the NP ‘breaks down’ along the length of the neurenteric canal. This process results in the notochordal plate (right), which retracts between the mesenchyme forming the definitive notochord. B Illustrates our proposed theory. All precursors of the notochord are simultaneously present. We now know that the NP is shorter in length and that the definitive notochord does not develop cranially in the embryo, but merely in the middle region (Figs 3 and 5). Definitive notochord (DN): red, endoderm: light grey (in sections), epiblast or ectoderm: dark blue, dark grey (in sections), gastrulation area (GA): purple, neurenteric canal: white, notochordal plate (NPL): yellow, notochordal process (NPR): cyan blue, prechordal plate (PP): brown.
	Fig 2. Development of the notochord in a stage 8 (17–19 days) human embryo.From left to right transversal illustrations, a schematic ventral view, transversal sections from specimen No. 7545 and a ventral view of a 3D reconstruction of specimen No. 5960. The embryo is viewed from ventral with the endoderm removed. Black lines indicate the level of the transversal sections (epiblast/ectoderm is superior in each transversal section). Subsequent to the gastrulation area (purple) the notochordal process (cyan blue) with a neurenteric canal (white on the schematic view and black arrow in the transversal sections) is present. The notochordal process is round, but further cranial it becomes smaller and the endoderm on its ventral side is hard to distinguish. Cranial in the embryo, the prechordal plate (brown) emerges as a cluster of mesenchymal cells. The prechoral plate can be identified in the 3D reconstruction as a broader structure cranial to the notochordal plate. Endoderm: light grey (in cross sections), epiblast or ectoderm: dark blue, dark grey (in transversal sections), gastrulation area (GA): purple, neurenteric canal: white, notochordal plate (NPL): yellow, notochordal process (NPR): cyan blue, prechordal plate (PP): brown.
	Fig 3. Development of the notochord in CS9 to CS12 (19–30 days).3D reconstructions of specimens Nos. 3709, 6330, 6344, and 8943. Black lines indicate the level of the transversal histological sections (neural ectoderm is superior in each section). A CS9 (19-21d.) embryo with notochordal plate tightly attached to the neural tube on both lateral sides, forming a flat or U-shaped notochordal plate around the developing neural tube. Caudally a notochordal process with a neurenteric canal, indicated with a black arrow. B CS10 (21-23d.) embryo, the notochordal ridges are now pointing ventral, giving the notochordal plate the inverted U-shape. C Left an early CS11 (23-26d.) embryo (sections of the reconstruction) with a definitive notochord in the middle of the embryo and notochordal plate on both cranial and caudal extremes. The late CS11 embryo (right) specimen No. 6344 has a definitive notochord at the caudal extreme and in the middle. D In CS12 (26-30d.) all sections show a definite notochord. The caudal part of the notochord has a larger diameter. Note the space between notochord and endoderm (black arrows) and between notochord and neural tube (dotted arrows). Endoderm: transparent green, gastrulation: purple, neural ectoderm: green, notochordal plate: yellow, Notochordal process: cyan blue.
	Fig 4. Overview of the developing notochord in relation to the fusion of the dorsal aortae.A 3D reconstruction of a stage 12 human embryo (26–30 days) specimen No. 8505A with ventrolateral view of the neural tube (green), the notochord (red) and dorsal aortae (purple) in the process of fusion. A part of the dorsal aorta is not fused at the dotted arrows, but cranial and caudal to this region the dorsal paired aortae are already fused. B A ventral close-up of the fusion process in stage 13 (28–32 days) human embryo specimen No. 836, which occurs in a ladder-like pattern. Small connections between the dorsal aortae can be appreciated (dotted arrows). C Transversal illustrations of the fusion of the paired dorsal aortae in relation to the developing notochord (ectoderm and is superior in each transversal section). During stages 8 to 12 (17–30 days) the paired dorsal aortae migrate from lateral to medial and fuse after the developing notochord is separated from the endoderm. Dorsal aorta: purple, definitive notochord (DN): red, neural ectoderm: green, notochordal plate (NPL): yellow, notochordal process (NPR): cyan blue.
	Fig 5. Schematic dorsal overview of the developing notochord and the fusion of the paired dorsal aortae in humans.In CS8 (17–19d.) the notochordal process is subsequent to the gastrulation area in direct contact with the prechordal plate. During CS8 to CS10 (17-23d.) the notochordal plate is formed between de notochordal process and the prechordal plate. Along with the axial lengthening of the whole embryo, the notochordal plate also lengthens, in contrast to the notochordal process. In CS10 to CS11 (21-26d.) the notochordal plate transformed into the definitive notochord, starting in the middle into both cranial and caudal direction. The cranial and caudal parts (triangular shaped) of the notochordal plate and definitive notochord are larger compared to the middle regions. In CS11 (23-26d.) the notochordal plate is cranially still present, in contrast to the caudal eminence (dotted box), where the definitive notochord is already formed due to the process of direct mesenchymal condensation. In this region the notochord is broader than in the middle and cranial region and contains more nuclei (Fig 3D). Definitive notochord: red, gastrulation: dark purple, neurenteric canal: white, notochordal plate: yellow, notochordal process: cyan blue, paired dorsal aortae: pink.
	Fig 6. Transversal sections of the notochord in a 24 hour stage chicken embryo from our lab.Caudally, gastrulation is still on-going, while cranial, the definitive notochord is already present in the same stage. Definitive notochord: red, gastrulation: purple.

References [+] :

Babić, Development of the notochord in normal and malformed human embryos and fetuses. 1991, Pubmed