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Neurenteric cysts account for 0.7-1.3% of spinal axis tumors. These uncommon lesions results from the inappropriate partitioning of the embryonic notochordal plate and presumptive endoderm during the third week of human development. Heterotopic nests of epithelium reminiscent of gastrointestinal and respiratory tissue lead to eventual formation of compressive cystic lesions of the pediatric and adult spine. We report a 40-year-old male presenting with slow-progressive myelopathic manifestation and ovoid non-enhancing cysticintradural extramedullary lesion at C7 level on MRI, mimicking intraspinal arachnoid cyst, who underwent successful surgical excision. The histopathological examination prove it to be neurenteric cyst.

The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not fully understood how these processes act together in a coordinated way during notochord formation. The prechordal plate is an actively migrating cell population in the central mesoderm anterior to the trailing notochordal plate cells. We show that prechordal plate cells express Protocadherin 18a (Pcdh18a), a member of the cadherin superfamily. We find that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms prechordal plate cells into a cohesive and fast migrating cell group. In turn, the prechordal plate cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation and extension of the posterior, axial cells. Indeed, a grafting experiment validated the prediction and local Pcdh18a expression induced an ectopic prechordal plate-like cell group migrating towards the animal pole. Our findings indicate that the Pcdh18a is important for prechordal plate formation, which influences the trailing mesodermal cell sheet by orchestrating the morphogenesis of the notochord. Electronic supplementary material The online version of this article (10.1007/s00418-020-01887-5) contains supplementary material, which is available to authorized users.

The notochord is a structure common to all chordates, and the feature that the phylum Chordata has been named after. It is a rod-like mesodermal structure that runs the anterior-posterior length of the embryo, adjacent to the ventral neural tube. The notochord plays a critical role in embryonic tissue patterning, for example the dorsal-ventral patterning of the neural tube. The cells that will come to form the notochord are specified at gastrulation. Axial mesodermal cells arising at the anterior primitive streak migrate anteriorly as the precursors of the notochord and populate the notochordal plate. Yet, even though a lot of interest has centered on investigating the functional and structural roles of the notochord, we still have a very rudimentary understanding of notochord morphogenesis. The events driving the formation of the notochord are rapid, taking place over the period of approximately a day in mice. In this commentary, we provide an overview of our current understanding of mouse notochord morphogenesis, from the initial specification of axial mesendodermal cells at the primitive streak, the emergence of these cells at the midline on the surface of the embryo, to their submergence and organization of the stereotypically positioned notochord. We will also discuss some key open questions. Developmental Dynamics 245:547-557, 2016. © 2016 Wiley Periodicals, Inc.

Nodal activity in the left lateral plate mesoderm is a conserved sign of irreversible left-right asymmetry at early somite stages of the vertebrate embryo. An earlier, paraxial nodal domain accompanies the emergence and initial extension of the notochord and is either left-sided, as in the chick and pig, or symmetrical, as in the mouse and rabbit; intriguingly, this interspecific dichotomy is mirrored by divergent morphological features of the posterior notochord (also known as the left-right organizer), which is ventrally exposed to the yolk sac cavity and carries motile cilia in the latter 2 species only. By introducing the cattle embryo as a new model organism for early left-right patterning, we present data to establish 2 groups of mammals characterized by both the morphology of the left-right organizer and the dynamics of paraxial nodal expression: presence and absence of a ventrally open surface of the early (plate-like) posterior notochord correlates with a symmetrical (in mice and rabbits) versus an asymmetrical (in pigs and cattle) paraxial nodal expression domain next to the notochordal plate. High-resolution histological analysis reveals that the latter domain defines in all 4 mammals a novel ‘parachordal' axial mesoderm compartment, the topography of which changes according to the specific regression of the similarly novel subchordal mesoderm during the initial phases of notochord development. In conclusion, the mammalian axial mesoderm compartment (1) shares critical conserved features despite the marked differences in early notochord morphology and early left-right patterning and (2) provides a dynamic topographical framework for nodal activity as part of the mammalian left-right organizer.

The post-implantation mouse embryo undergoes major shape changes after the initiation of gastrulation and morphogenesis. A hallmark of morphogenesis is the formation of the transient organizers, the node and notochordal plate, from cells that have passed through the primitive streak. The proper formation of these signaling centers is essential for the development of the body plan and techniques to visualize them are of high interest to mouse developmental biologists. The node and notochordal plate lie on the ventral surface of gastrulating mouse embryos around embryonic day (E) 7.5 of development. The node is a cup-shaped structure whose cells possess a single slender cilium each. The proper subcellular localization and rotation of the cilia in the node pit determines left-right asymmetry. The notochordal plate cells also possess single cilia albeit shorter than those of the node cells. The notochordal plate forms the notochord which acts as an important signaling organizer for somitogenesis and neural patterning. Because the cells of the node and notochordal plate are transiently present on the surface and possess cilia, they can be visualized using scanning electron microscopy (SEM). Among other techniques used to visualize these structures at the cellular level is whole mount immunofluorescence (WMIF) using the antibodies against the proteins that are highly expressed in the node and notochordal plate. In this report, we describe our optimized protocols to perform SEM and WMIF of the node and notochordal plate in developing mouse embryos to help in the assessment of tissue shape and cellular organization in wild-type and gastrulation mutant embryos.

Existence and biomedical relevance of the neurenteric canal, a transient midline structure during early neurulation in the human embryo, have been controversially discussed for more than a century by embryologists and clinicians alike. In this study, the authors address the long-standing enigma by high-resolution histology and three-dimensional reconstruction using new and historic histological sections of 5 human 17- to 21-day-old embryos and of 2 marmoset monkey embryos of the species Callithrix jacchus at corresponding stages. The neurenteric canal presents itself as the classical vertical connection between the amniotic cavity and the yolk sac cavity and is lined (a) craniolaterally by a horseshoe-shaped “hinge of involuting notochordal cells” within Hensen’s node and (b) caudally by the receding primitive streak epiblast dorsally and by notochordal plate epithelium ventrally, the latter of which covered the (longitudinal) notochordal canal on its ventral side at the preceding stage. Furthermore, asymmetric parachordal nodal expression in Callithrix and morphological asymmetries within the nodes of the other specimens suggest an early non-cilium-dependent left-right symmetry breaking mode previously postulated for other mammals. We conclude that structure and position of the mammalian neurenteric canal support the notion of its homology with the reptilian blastopore as a whole and with a dorsal segment of the blastopore in amphibia. These new features of the neurenteric canal may further clarify the aetiology of foetal malformations such as junctional neurulation defects, neuroendodermal cysts, and the split notochord syndrome.

The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not known how these processes act together in a coordinated way during notochord formation. Analysing the tissue flow, we determined the displacement of the axial mesoderm and identified, relative to the ectoderm, an actively-migrating notochord tip cell population and a group of trailing notochordal plate cells. Molecularly, these tip cells express Protocadherin18a, a member of the cadherin superfamily. We show that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms these tip cells into a cohesive and fast migrating cell group. In turn, these tip cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework, and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation of the posterior, axial cells. Indeed, grafting experiments validated the predictions and induced ectopic notochord-like rods. Our findings indicate that the tip cells influence the trailing mesodermal cell sheet by inducing the formation of the notochord.

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.

Many internal organs develop distinct left and right sides that are essential for their functions. In several vertebrate embryos, motile cilia generate an asymmetric fluid flow that plays an important role in establishing left-right (LR) signaling cascades. These ‘LR cilia’ are found in the ventral node and posterior notochordal plate in mammals, the gastrocoel roof plate in amphibians and Kupffer’s vesicle in teleost fish. I consider these transient ciliated structures as the ‘organ of asymmetry’ that directs LR patterning of the developing embryo. Variations in size and morphology of the organ of asymmetry in different vertebrate species have raised questions regarding the fundamental features that are required for LR determination. Here, I review current models for how LR asymmetry is established in vertebrates, discuss the cellular architecture of the ciliated organ of asymmetry and then propose key features of this organ that are critical for orienting the LR body axis.

Establishment of left-right asymmetry in the mouse embryo depends on leftward laminar fluid flow in the node, which initiates a signaling cascade that is confined to the left side of the embryo. Leftward fluid flow depends on two cellular processes: motility of the cilia that generate the flow and morphogenesis of the node, the structure where the cilia reside. Here, we provide an overview of the current understanding and unresolved questions about the regulation of ciliary motility and node structure. Analysis of mouse mutants has shown that the motile cilia must have a specific structure and length, and that they must point posteriorly to generate the necessary leftward fluid flow. However, the precise structure of the motile cilia is not clear and the mechanisms that position cilia on node cells have not been defined. The mouse node is a teardrop-shaped pit at the distal tip of the early embryo, but the morphogenetic events that create the mature node from cells derived from the primitive streak are only beginning to be characterized. Recent live imaging experiments support earlier scanning electron microscopy (SEM) studies and show that node assembly is a multi-step process in which clusters of node precursors appear on the embryo surface as overlying endoderm cells are removed. We present additional SEM and confocal microscopy studies that help define the transition stages during node morphogenesis. After the initiation of left-sided signaling, the notochordal plate, which is contiguous with the node, generates a barrier at the embryonic midline that restricts the cascade of gene expression to the left side of the embryo. The field is now poised to dissect the genetic and cellular mechanisms that create and organize the specialized cells of the node and midline that are essential for left-right asymmetry.

The brain, heart and gastro-intestinal tract develop distinct left–right (LR) asymmetries. Asymmetric cilia-dependent fluid flow in the embryonic node in mouse, Kupffer's vesicle in zebrafish, notochordal plate in rabbit and gastrocoel roof plate in frog appears to be a conserved mechanism that directs LR asymmetric gene expression and establishes the orientation of organ asymmetry. However, the cellular processes and genetic pathways that control the formation of these essential ciliated structures are unknown. In zebrafish, migratory dorsal forerunner cells (DFCs) give rise to Kupffer's vesicle (KV), a ciliated epithelial sheet that forms a lumen and generates fluid flow. Using the epithelial marker atypical Protein Kinase C (aPKC) and other markers to analyze DFCs and KV cells, we describe a multi-step process by which DFCs form a functional KV. Using mutants and morpholinos, we show that two T-box transcription factors–No tail (Ntl)/Brachyury and Tbx16/Spadetail–cooperatively regulate an early step of DFC mesenchyme to epithelial transition (MET) and KV cell specification. Subsequently, each transcription factor independently controls a distinct step in KV formation: Tbx16 regulates apical clustering of KV cells and Ntl is necessary for KV lumen formation. By targeting morpholinos to DFCs, we show that these cell autonomous functions in KV morphogenesis are necessary for LR patterning throughout the embryo.

The mammalian node, the functional equivalent of the frog dorsal blastoporal lip (Spemann's organizer), was originally described by Viktor Hensen in 1876 in the rabbit embryo as a mass of cells at the anterior end of the primitive streak. Today, the term "node" is commonly used to describe a bilaminar epithelial groove presenting itself as an indentation or "pit" at the distal tip of the mouse egg cylinder, and cilia on its ventral side are held responsible for molecular laterality (left-right) determination. We find that Hensen's node in the rabbit is devoid of cilia, and that ciliated cells are restricted to the notochordal plate, which emerges from the node rostrally. In a comparative approach, we use the organizer marker gene Goosecoid (Gsc) to show that a region of densely packed epithelium-like cells at the anterior end of the primitive streak represents the node in mouse and rabbit and is covered ventrally by a hypoblast (termed "visceral endoderm" in the mouse). Expression of Nodal, a gene intricately involved in the determination of vertebrate laterality, delineates the wide plate-like posterior segment of the notochord in the rabbit and mouse, which in the latter is represented by the indentation frequently termed "the node." Similarly characteristic ciliation and nodal expression exists in Xenopus neurula embryos in the gastrocoel roof plate (GRP), i.e., at the posterior end of the notochord anterior to the blastoporal lip. Our data suggest that (1) a posterior segment of the notochord, here termed PNC (for posterior notochord), is characterized by features known to be involved in laterality determination, (2) the GRP in Xenopus is equivalent to the mammalian PNC, and (3) the mammalian node as defined by organizer gene expression is devoid of cilia and most likely not directly involved in laterality determination.

Motile monocilia play a pivotal role in left-right axis determination in mouse and zebrafish embryos. Cilia with 9+0 axonemes localize to the distal indentation of the mouse egg cylinder ("node"), while Kupffer's vesicle cilia in zebrafish show 9+2 arrangements. Here we studied cilia in a prototype mammalian embryo, the rabbit, which develops via a flat blastodisc. Transcription of ciliary marker genes Foxj1, Rfx3, lrd, polaris, and Kif3a initiated in Hensen's node and persisted in the nascent notochord. Cilia emerged on cells leaving Hensen's node anteriorly to form the notochordal plate. Cilia lengthened to about 5 mum and polarized from an initially central position to the posterior pole of cells. Electron-microscopic analysis revealed 9+0 and 9+2 cilia and a novel 9+4 axoneme intermingled in a salt-and-pepper-like fashion. Our data suggest that despite a highly conserved ciliogenic program, which initiates in the organizer, axonemal structures may vary widely within the vertebrates.

Danforth’s short tail (Sd) is a semidominant mutation in mouse affecting the axial skeleton and urogenital system. The notochord is the first visibly abnormal structure in mutant embryos, and disintegrates beginning around embryonic day 9.5 along its entire length, suggesting an essential role for Sd in notochord development and main-tenance. Here, we report on the fate of Sd/+ and Sd/Sd cells in chimeric embryos. Up to day 9-9.5, Sd cells contributed effi-ciently to the notochord of chimeric embryos. In advanced day 9.5 embryos, Sd cells were less abundant in the posterior-most region of the notochord and in the noto-chordal plate. During subsequent development, Sd cells were specifically lost from the notochord and replaced by wild-type cells. In Sd/+↔+/+ chimeras, the notochord appeared histologically and functionally normal, leading to a rescue of the mutant phenotype. However, strong Sd/Sd↔+/+ chimeras showed malformations of the axial skeleton and urogenital system. All Sd/Sd↔+/+ chimeras with malformations of the axial skeleton also had kidney defects, whereas chimeras without vertebral column defects had highly chimeric kidneys that appeared normal, suggesting that the urogenital malformations arise secon-darily to impaired posterior development caused by the degenerating notochord. Sd mutant cells also were specifi-cally absent from the ventral portion of the hindgut, whereas they contributed efficiently to the dorsal region, implying the existence of distinct cell populations in the dorsal and ventral hindgut. Our findings demonstrate that the Sd mutation acts cell autonomously in cells of the notochord and ventral hind gut. Sd leads to the degeneration of notochord cells and the number or allocation of notochord precursors from the tail bud to the notochordal plate seems impaired, whereas notochord formation from the node appears to be unaffected.

Despite a wealth of information about cell behaviors contributing to neurulation in chick embryos, similar behaviors in mouse embryos have yet to be well characterized. This study examines cell behaviors occurring during bending of the mouse neural plate, in particular, qualitative and quantitative changes in neuroepithelial cell shape. Our current results demonstrate that in mouse embryos (1) the median hinge point (MHP), a localized region of neural plate that becomes anchored to the underlying prechordal plate mesoderm or notochord/ notochordal plate and forms a midline longitudinal furrow around which folding of the remaining neural plate (i.e., the part of the neural plate not involved in MHP formation) occurs, develops during stages of neural fold elevation; (2) the MHP is enriched with wedge-shaped neuroepithelial cells but has significantly fewer spindle-shaped, inverted wedge-shaped, and globular neuroepithelial cells than do the adjacent paired lateral areas of the neuroepithelium (L); and (3) each L is enriched with spindle-shaped, inverted wedge-shaped, and globular neuroepithelial cells but has significantly fewer wedge-shaped neuroepithelial cells than does the MHP. Thus wedging of neuroepithelial cells occurs during bending of the mouse neural plate and is localized to the MHP during neural fold elevation. Similarly, previous studies in the chick have shown that neuroepithelial cells become wedge shaped during bending of the neural plate and that such cell wedging is localized to the MHP during neural fold elevation. Such studies also have shed light on the roles of MHP formation and localized wedging of neuroepithelial cells within the MHP in the chick; however, such roles have yet to be elucidated in the mouse. It is probable that the MHP in mouse embryos, like that in chick embryos, provides a locus for bending of the neural plate and that wedging of neuroepithelial cells within the MHP provides the force necessary to generate the longitudinal midline furrow around which subsequent folding of the neural plate (i.e., neural fold elevation) occurs. Further studies are necessary to define these roles more precisely. © 1994 Wiley-Liss, Inc.

A common element during early left–right patterning of the vertebrate body is left-sided nodal expression in the early-somite stage lateral plate mesoderm. Leftward cell movements near the node of the gastrulating chick embryo recently offered a plausible mechanism for breaking the presomite-stage molecular symmetry in those vertebrates which lack rotating cilia on the notochord or equivalent tissues. However, the temporal and functional relationships between generation of the known morphological node asymmetry, onset of leftward cell movements and establishment of stable molecular asymmetry in the chick remain unresolved. This study uses high-resolution light microscopy and in situ gene expression analysis to show that intranodal cell rearrangement during the phase of counter-clockwise node torsion at stage 4+ is immediately followed by symmetry loss and rearrangement of shh and fgf8 expression in node epiblast between stages 5− and 5+. Surprisingly, left-sided nodal expression starts at stage 5−, too, but lies in the paraxial mesoderm next to the forming notochordal plate, and can be rendered symmetrical by minimal mechanical disturbance of distant tissue integrity at stage 4. The “premature” paraxial nodal expression together with morphological and molecular asymmetries in, and near, midline compartments occurring at defined substages of early gastrulation help to identify a new narrow time window for early steps in left–right patterning in the chick and support the concept of a causal relationship between a—still enigmatic—chiral (motor) protein, cell movements and incipient left–right asymmetry in the amniote embryo.

Human foregut malformation known as esophageal atresia with tracheoesophageal fistula (EA/TEF) occurs in 1 in 4,000 live births with unknown etiology. We found that mice lacking Noggin (Nog(-/-)) displayed Type C EA/TEF, the most common form in humans, and notochordal defects strikingly similar to the adriamycin-induced rat EA/TEF model. In accord with esophageal atresia, Nog(-/-) embryos displayed reduction in the dorsal foregut endoderm, which was associated with reduced adhesion and disrupted basement membrane. However, significant apoptosis in the Nog(-/-) dorsal foregut was not observed. Instead, non-notochordal, likely endodermal, cells were found in Nog(-/-) notochord, suggesting that Noggin function is required in the notochordal plate for its proper delamination from the dorsal foregut. Notably, ablating Bmp7 function in Nog(-/-) embryos rescued EA/TEF and notochord branching defects, establishing a critical role of Noggin-mediated Bmp7 antagonism in EA/TEF pathogenesis.

Development of the node and formation of the notochordal plate in gestational day 7-9 mice (Theiler stages 10-14) has been documented principally with scanning electron microscopy (SEM) and cell fate analyses utilizing DiI and/or CFSE as a cell label. With SEM, cells composing these two populations are initially identifiable at stage 10 at the ventral midline of the rostral half of the embryo. They can be recognized by their relatively small ventral surface area, as compared to that of the peripherally adjacent prospective gut endodermal cells, and by the presence on the ventral side of each cell of a prominent single, central cilium, which is lacking on endodermal cells. At stage 10, the node is located at the apex of the cup-shaped embryo. It represents the rostral end of the primitive streak (although its structure differs from that of the rest of the streak), and it consists of a localized two-layered area (i.e., epiblast and the most caudal aspect of the notochordal plate). By stage 11, the notochordal plate constitutes a relatively broad, circular area (at the level of the node) that tapers rostrally into a narrower midline strip (beneath the future floor plate of the neural tube). The tip of the notochordal plate terminates rostrally at the much broader prechordal plate, which underlies the future forebrain level of the neuraxis. The prechordal plate cells, like the ventral node and notochordal plate cells, each have a relatively small ventral surface area and displays a single central cilium on their ventral surface. The most caudal aspect of the notochordal plate remains morphologically distinct on the dorsal, midline surface of the open gut through stage 13; the more rostral levels progressively fold off from the roof of the gut to form the definitive notochord. Videomicroscopy reveals that the cilia extending from the ventral surfaces of the cells of node and of the prechordal and notochordal plates are motile. The potential significance of this motile behavior remains unknown. Labeling studies, which marked cells in both the dorsal and ventral layers of the node, reveal that the stage-10 node contributes cells to the notochordal plate and overlying midline ectodermal cells of the neural plate, the future floor plate of the neural tube.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: Formation and extension of the notochord (i.e., notogenesis) is one of the earliest and most obvious events of axis development in vertebrate embryos. In birds and mammals, prospective notochord cells arise from Hensen's node and come to lie beneath the midline of the neural plate. Throughout the period of neurulation, the notochord retains its close spatial relationship with the developing neural tube and undergoes rapid extension in concert with the overlying neuroepithelium. Methods: In the present study, we examined notochord development quantitatively in mouse embryos. C57BL/6 mouse embryos were collected at 8, 8.5, 9, 9.5, and 10 days of gestation. They were then embedded in paraffin and sectioned transversely. Serial sections from 21 embryos were stained with Schiff's reagent according to the Feulgen-Rossenbeck procedure and used for quantitative analyses of notochord extension. Results: Quantitative analyses revealed that extension of the notochord involves cell division within the notochord proper and cell rearrangement within the notochordal plate (the immediate precursor of the notochord). In addition, extension of the notochord involves cell accretion, that is, the addition of cells to the notochord's caudal end, a process that involves considerable cell rearrangement at the notochordal plate-node interface. Conclusions: Extension of the mouse notochord occurs similarly to that described previously for birds (Sausedo and Schoenwolf, 1993 Anat. Rec. 237:58–70). That is, in both birds (i.e., quail and chick) and mouse embryos, notochord extension involves cell division, cell rearrangement, and cell accretion. Thus higher vertebrates utilize similar morphogenetic movements to effect notogenesis. © 1994 Wiley-Liss, Inc.

Neurenteric cysts account for 0.7-1.3% of spinal axis tumors. These rare lesions result from the inappropriate partitioning of the embryonic notochordal plate and presumptive endoderm during the third week of human development. Heterotopic rests of epithelium reminiscent of gastrointestinal and respiratory tissue lead to eventual formation of compressive cystic lesions of the pediatric and adult spine. Histopathological analysis of neurenteric tissue reveals a highly characteristic structure of columnar or cuboidal epithelium with or without cilia and mucus globules. Patients with symptomatic neurenteric cysts typically present in the second and third decades of life with size-dependent myelopathic and/or radicular signs. Magnetic resonance imaging and computed tomography are essential diagnostic tools for the delineation of cyst form and overlying osseous architecture. A variety of approaches have been employed in the treatment of neurenteric cysts each with a goal of total surgical resection. Although long-term outcome analyses are limited, data available indicate that surgical intervention in the case of neurenteric cysts results in a high frequency of resolution of neurological deficit with minimal morbidity. However, recurrence rates as high as 37% have been reported with incomplete resection secondary to factors such as cyst adhesion to surrounding structure and unclear dissection planes. Here we present a systematic review of English language literature from January 1966 to December 2009 utilizing MEDLINE with the following search terminology: neurenteric cyst, enterogenous cyst, spinal cord tumor, spinal dysraphism, intraspinal cyst, intramedullary cyst, and intradural cyst. In addition, the references of publications returned from the MEDLINE search criteria were surveyed in order to examine other pertinent reports.

Presence of keratin was observed in the notochordal plate of 10-day rat embryos. The characteristic changes in the appearance of the notochord during the following days of gestation were also observed in sections stained by immunofluorescence with keratin antisera. On day 12, the keratin-positive notochordal plate had become a cylindrical structure closely apposed to the ventral surface of the spinal cord. The distance between notochord and spinal cord progressively increased at later stages. The expression of keratin was also studied by the Avidin-Biotin complex method on 4 chordomas, tumors originating from intraosseous notochordal vestigial remnants. In accordance with the developmental study all chordomas were keratin-positive.

Five embryos of stage 9 (20 days) were studied in detail and graphic reconstructions were prepared. This is the first report based on more than one specimen of this rarely seen stage. Detailed measurements of the embryos are provided. The characteristic features of this stage are 1 to 3 pairs of somites, the head fold and foregut, the otic discs, and the pericardial cavity. The primitive streak is not decreasing as rapidly as in stage 8 but the caudal eminence is proliferating. The notochordal plate is not increasing as rapidly as in stage 8 and a notochord is not yet present. It is to be stressed that the 3 major divisions of the brain (prosencephalic, mesencephalic, and rhombencephalic) can be identified in the open neural groove. The rhombencephalon is the dominant feature of the brain and comprises 4 subdivisions, the last of which, previously unrecognized, is related to the (occipital) somites and represents the hypoglossal region. Features that may not be visible include the caudal fold and hindgut, endocardial tubes or plexus, neural crest, and neurenteric canal. In 2 specimens, atria, left ventricle, right ventricle, conotruncus, and first (or first and second) aortic arches are distinguishable. Two of the embryos studied are the earliest examples in which neural crest has been identified.

In a former memoir (1934) the author described the early development of the ferret from fertilisation to the formation of the prochordal plate. The following is a continuation of that work and describes the development of the mesoblast and notochord from their incipient phases to a stage with seven somites when the definitive notochord begins to separate from the notochordal plate. As far as can be ascertained these phases have not been previously described in the case of the ferret, although the literature on gastrulation and the formation of the notochord and mesoblast is voluminous. A résumé of the descriptions and theories of gastrulation has already been fully summarised by Rabl (1915), and later by Van Oordt (1921). Opinions concerning notochord and mesoblast formation will be referred to in the following pages, and as there is great confusion of nomenclature in it I have appended a Glossary of the terms which I have used and the meanings that I attach to them (p. 188).

Serial sections of 60 bovine embryos (23 timed specimens) from 17 through 34 days gestation were examined to determine the processes and sequence of notochord development. Head notochord formed during days 18 through 21 as the ventral-most layer of cells from Hensen's node became intercalated as the notochordal plate between the endodermal cells of the primitive open gut. The notochordal plate responded to contact by the neural plate during day 20 with hypertrophy of notochordal cells and a ventral curving of the notochordal plate margins to form the notochordal ridge which appeared as a dorsal evagination of the gut, but was not endodermal. Formation of the head notochord into a rod (without a notochordal canal or pit) occurred during days 20 and 21 reuniting the endodermal layer ventral to the notochord. Body notochord formed during days 21 through 32–33 caudad from the level of somite pair 6 by accumulation of notochordal cells from Hensen's node directly into a rod surrounded by a basal lamina without contact or penetration of the gut endoderm. Bovine notochord was, thus, formed by two methods. After formation by both methods, the notochord enlarged by proliferation of its own cells. Dorso-ventral undulations of the notochord became distinct by the 27th day. The processes involved in bovine notochord development were different from descriptions published concerning other species in that 1. two methods of formation were found, and 2. notochordal plate formation preceded notochordal ridge production rather than vice versa.

We have examined the role of Furin in postimplantation-stage mouse embryos by analyzing both the expression pattern of fur mRNA and the developmental consequences of a loss-of-function mutation at the fur locus. At early stages (day 7.5), fur mRNA is abundant in extraembryonic endoderm and mesoderm, anterior visceral endoderm, and in precardiac mesoderm. 1 day later fur is expressed throughout the heart tube and in the lateral plate mesoderm, notochordal plate and definitive gut endoderm. Embryos lacking Furin die between days 10.5 and 11.5, presumably due to hemodynamic insufficiency associated with severe ventral closure defects and the failure of the heart tube to fuse and undergo looping morphogenesis. Morphogenesis of the yolk sac vasculature is also abnormal, although blood islands and endothelial precursors form. Analysis of cardiac and endodermal marker genes shows that while both myocardial precursors and definitive endoderm cells are specified, their numbers and migratory properties are compromised. Notably, mutant embryos fail to undergo axial rotation, even though Nodal and eHand, two molecular markers of left-right asymmetry, are appropriately expressed. Overall, the present data identify Furin as an important activator of signals responsible for ventral closure and embryonic turning.