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Concept: Neurulation


During neural tube formation, neural plate cells migrate from the lateral aspects of the dorsal surface towards the midline. Elevation of the lateral regions of the neural plate produces the neural folds which then migrate to the midline where they fuse at their dorsal tips, generating a closed neural tube comprising an apicobasally polarized neuroepithelium. Our previous study identified a novel role for the axon guidance receptor neogenin in Xenopus neural tube formation. We demonstrated that loss of neogenin impeded neural fold apposition and neural tube closure. This study also revealed that neogenin, via its interaction with its ligand, RGMa, promoted cell-cell adhesion between neural plate cells as the neural folds elevated and between neuroepithelial cells within the neural tube. The second neogenin ligand, netrin-1, has been implicated in cell migration and epithelial morphogenesis. Therefore, we hypothesized that netrin-1 may also act as a ligand for neogenin during neurulation. Here we demonstrate that morpholino knockdown of Xenopus netrin-1 results in delayed neural fold apposition and neural tube closure. We further show that netrin-1 functions in the same pathway as neogenin and RGMa during neurulation. However, contrary to the role of neogenin-RGMa interactions, neogenin-netrin-1 interactions are not required for neural fold elevation or adhesion between neuroepithelial cells. Instead, our data suggest that netrin-1 contributes to the migration of the neural folds towards the midline. We conclude that both neogenin ligands work synergistically to ensure neural tube closure. © 2012 Wiley Periodicals, Inc., 2013.

Concepts: Axon, Embryology, Neural tube, Neurulation, Developmental neuroscience, Neural plate, Neural folds, Neural groove


Early in the development of the central nervous system, progenitor cells undergo a shape change, called apical constriction, that triggers the neural plate to form a tubular structure. How apical constriction in the neural plate is controlled, and contributes to tissue morphogenesis, are not fully understood. In this study, we show that intracellular calcium ions (Ca(2+)) are required for Xenopus neural tube formation, and that there are two types of Ca(2+)-concentration changes, a single-cell and a multicellular wave-like fluctuation, in the developing neural plate. Quantitative imaging analyses revealed that transient increases in Ca(2+) concentration induced cortical F-actin remodeling, apical constriction, and accelerations of the closing movement of the neural plate. We also show that extracellular ATP and N-cadherin participate in the Ca(2+)-induced apical constriction. Furthermore, our mathematical model suggests that the effect of Ca(2+) fluctuations on tissue morphogenesis was independent of its frequency, and fluctuations affecting individual cells were more efficient than those at the multicellular level. We propose that distinct Ca(2+) signaling patterns differentially modulate apical constriction for efficient epithelial folding and this mechanism has broad physiological outcomes.

Concepts: Central nervous system, Nervous system, Neuron, Brain, Developmental biology, Cellular differentiation, Neural tube, Neurulation


Ectothermal reptiles have internal pigmentation, which is not seen in endothermal birds and mammals. Here we show that the development of the dorsal neural tube-derived melanoblasts in turtle Trachemys scripta is regulated by similar mechanisms as in other amniotes, but significantly later in development, during the second phase of turtle trunk neural crest emigration. The development of melanoblasts coincided with a morphological change in the dorsal neural tube between stages mature G15 and G16. The melanoblasts delaminated and gathered in the carapacial staging area above the neural tube at G16, and differentiated into pigment-forming melanocytes during in vitro culture. The Mitf-positive melanoblasts were not restricted to the dorsolateral pathway as in birds and mammals but were also present medially through the somites similarly to ectothermal anamniotes. This matched a lack of environmental barrier dorsal and lateral to neural tube and the somites that is normally formed by PNA-binding proteins that block entry to medial pathways. PNA-binding proteins may also participate in the patterning of the carapacial pigmentation as both the migratory neural crest cells and pigment localized only to PNA-free areas.

Concepts: Embryo, Developmental biology, Reptile, Ectoderm, Neural tube, Neural crest, Amniote, Neurulation


During vertebrate development, trunk neural crest cells delaminate along the entire length of the dorsal neural tube and initially migrate as a non-segmented sheet. As they enter the somites, neural crest cells rearrange into spatially restricted segmental streams. Extracellular matrix components are likely to play critical roles in this transition from a sheet-like to a stream-like mode of migration, yet the extracellular matrix components and their modifying enzymes critical for this transition are largely unknown. Here, we identified the glycosyltransferase Lh3, known to modify extracellular matrix components, and its presumptive substrate Collagen18A1, to provide extrinsic signals critical for neural crest cells to transition from a sheet-like migration behavior to migrating as a segmental stream. Using live cell imaging we show that in lh3 null mutants, neural crest cells fail to transition from a sheet to a stream, and that they consequently enter the somites as multiple streams, or stall shortly after entering the somites. Moreover, we demonstrate that transgenic expression of lh3 in a small subset of somitic cells adjacent to where neural crest cells switch from sheet to stream migration restores segmental neural crest cell migration. Finally, we show that knockdown of the presumptive Lh3 substrate Collagen18A1 recapitulates the neural crest cell migration defects observed in lh3 mutants, consistent with the notion that Lh3 exerts its effect on neural crest cell migration by regulating post-translational modifications of Collagen18A1. Together these data suggest that Lh3-Collagen18A1 dependent ECM modifications regulate the transition of trunk neural crest cells from a non-segmental sheet like migration mode to a segmental stream migration mode.

Concepts: Enzyme, Embryo, Extracellular matrix, Developmental biology, Ectoderm, Neural tube, Neural crest, Neurulation


The notochord has organizer properties and is required for floor plate induction and dorsoventral patterning of the neural tube. This activity has been attributed to sonic hedgehog (shh) signaling, which originates in the notochord, forms a gradient, and autoinduces shh expression in the floor plate. However, reported data are inconsistent and the spatiotemporal development of the relevant shh expression domains has not been studied in detail. We therefore studied the expression dynamics of shh in rabbit, chicken and Xenopus laevis embryos (as well as indian hedgehog and desert hedgehog as possible alternative functional candidates in the chicken).

Concepts: Spinal cord, Developmental biology, Cellular differentiation, Embryology, Sonic hedgehog, Erinaceidae, Neurulation, Zona limitans intrathalamica


Early vertebrate embryos possess cells with the potential to generate all embryonic cell types. While this pluripotency is progressively lost as cells become lineage restricted, Neural Crest cells retain broad developmental potential. Here, we provide novel insights into signals essential for both pluripotency and neural crest formation in Xenopus. We show that FGF signaling controls a subset of genes expressed by pluripotent blastula cells, and find a striking switch in the signaling cascades activated by FGF signaling as cells lose pluripotency and commence lineage restriction. Pluripotent cells display and require Map Kinase signaling, whereas PI3 Kinase/Akt signals increase as developmental potential is restricted, and are required for transit to certain lineage restricted states. Importantly, retaining a high Map Kinase/low Akt signaling profile is essential for establishing Neural Crest stem cells. These findings shed important light on the signal-mediated control of pluripotency and the molecular mechanisms governing genesis of Neural Crest.

Concepts: Cell, Embryo, Developmental biology, Stem cell, Cell biology, Embryonic stem cell, Pluripotency, Neurulation


Neural crest (NC) specification comprises an early phase, initiating immature NC progenitors formation at neural plate stage, and a later phase at neural fold stage, resulting into functional premigratory NC, able to delaminate and migrate. We found that the NC Gene Regulatory Network triggers up-regulation of pfkfb4 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4) during this late specification phase. As shown in previous studies, PFKFB4 controls AKT signaling in gastrulas and glycolysis rate in adult cells. Here, we focus on PFKFB4 function in NC during and after neurulation, using time-controlled or hypomorph depletions in vivo We find that PFKFB4 is essential both for specification of functional premigratory NC and for its migration. PFKFB4-depleted embryos fail activating n-cadherin and late NC specifiers, exhibit severe migration defects, resulting in craniofacial defects. AKT signaling mediates PFKFB4 function in NC late specification, while both AKT signaling and glycolysis regulate migration. These findings highlight novel and critical roles of PFKFB4 activity in later stages of NC development, wired into the NC-GRN.

Concepts: Embryo, Embryology, Regulation, Neural tube, Neurulation, Neural plate, Neural folds


Folate supplementation prevents up to 70% of neural tube defects (NTDs), which result from a failure of neural tube closure during embryogenesis. The elucidation of the mechanisms underlying folate action has been challenging. This study introduces Xenopus laevis as a model to determine the cellular and molecular mechanisms involved in folate action during neural tube formation. We show that knockdown of folate receptor-α (FRα) impairs neural tube formation and leads to NTDs. FRα knockdown in neural plate cells only is necessary and sufficient to induce NTDs. FRα-deficient neural plate cells fail to constrict, resulting in widening of the neural plate midline and defective neural tube closure. Pharmacological inhibition of folate action by methotrexate during neurulation induces NTDs by inhibiting folate interaction with its uptake systems. Our findings support a model for folate receptor interacting with cell adhesion molecules, thus regulating apical cell membrane remodeling and cytoskeletal dynamics necessary for neural plate folding. Further studies in this organism may unveil novel cellular and molecular events mediated by folate and lead to new means for preventing NTDs.

Concepts: Protein, Gene, Bacteria, Cytosol, Cell membrane, Cytoplasm, Neural tube, Neurulation


A discontinuous, functionally disconnected spinal cord is an extremely rare finding, with only three known reports in the literature. Titled junctional neural tube defect (JNTD), this newly reported dysraphism is believed to arise from a developmental error occurring during junctional neurulation, a transitory stage of development marked by the end of primary neurulation and the beginning of secondary neurulation. Herein, we report a newborn case of JNTD.

Concepts: Central nervous system, Spinal cord, Developmental biology, Report, Developmental psychology, Neural tube, Neural tube defect, Neurulation


OBJECTIVE Spinal lipomas are generally thought to occur as a result of failed primary neurulation. However, some clinical features cannot be explained by this theory. The authors propose a novel classification of spinal lipomas based on embryonic changes seen during primary and secondary neurulation. METHODS A total of 677 patients with occult spinal dysraphism underwent 699 surgeries between August 2002 and May 2015 at the National Center for Child Health and Development and Tokyo Metropolitan Children’s Medical Center. This group of patients had 378 spinal lipomas, including 119 conus spinal lipomas, 27 lipomyelomeningoceles, and 232 filum lipomas, which the authors classified into 4 types based on neural tube formation during embryonic development. Type 1 is defined as pure primary neurulation failure; Type 2 ranges from primary to secondary neurulation failure; Type 3 consists of secondary neurulation failure (early phase); and Type 4 is defined as secondary neurulation failure (late phase). The authors also review embryogenesis in secondary neurulation and analyze the clinical utility of the new classification. RESULTS There were 55 Type 1 spinal lipomas, 29 Type 2, 62 Type 3, and 232 Type 4. All filum lipomas fell into the Type 4 spinal lipoma category. Association with anorectal and/or sacral anomalies was seen in none of the Type 1 cases, 15 (52%) of Type 2, 35 (56%) of Type 3, and 31 (13%) of Type 4. Urogenital anomalies were observed in none of the Type 1 or Type 2 cases, 1 (2%) of Type 3, and 28 (12%) of Type 4. Anomaly syndromes were present in none of the Type 1 cases, 6 (21%) of Type 2, 3 (5%) of Type 3, and 16 (7%) of Type 4. Associated anomalies or anomaly syndromes were clearly observed only for Type 2-4 spinal lipomas encompassing failed secondary neurulation. Radical resection was feasible for Type 1 spinal lipomas. CONCLUSIONS Secondary neurulation of the spinal cord gives rise to the conus medullaris and filum terminale, which are often involved in spinal lipomas. Formation of spinal lipomas seems to be a continuous process overlapping primary and secondary neurulation in some cases. Association with other anomalies was higher in Type 2-4 spinal lipomas, which included failed secondary neurulation, than in Type 1 lipomas, with failed primary neurulation. On the other hand, radical resection was indicated for Type 1, but not for Type 2, spinal lipomas. The new classification of spinal lipomas based on embryonic stage has the potential for clinical use and agrees well with both clinical and surgical findings. The classification proposed here is still preliminary. Further studies and verification are necessary to establish its clinical utility.

Concepts: Central nervous system, Spinal cord, Paralysis, Neural tube, Cauda equina, Filum terminale, Conus medullaris, Neurulation