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PubMed1988

Microsurgical analyses of avian neurulation: separation of medial and lateral tissues.

Neurulation, formation of the neural tube, is a complex process involving shaping and bending of the neural plate and closure of the neural groove. We have used avian embryos as model systems to study this process. In the present investigation, blastoderms were cut parasagittally through their entire thickness, either unilaterally or bilaterally, at two mediolateral locations: 1) at the juncture between prospective neural plate and prospective surface epithelium, and 2) at the juncture between the midline strip of prospective neural plate and more lateral prospective neural plate. In the first experiment, shaping of the neural plate seemed normal, but elevation and convergence of the neural folds and closure of the neural groove were inhibited (except at the forebrain level). This result demonstrates that extrinsic forces generated by lateral tissues are required for neural plate bending and neural groove closure. In the second experiment, neuroepithelial cells within the isolated, midline strip became wedge shaped. This result indicates that neuroepithelial cell "wedging" is an active event occurring independently of forces generated by elevation of the neural folds. Additional studies are required to define the natures of neurulation forces and the mechanisms by which they are generated.

Animals↗

PubMed1976

A scanning electron microscopic and flame spectrometry study on the role of Ca2+ in amphibian neurulation using papaverine inhibition and ionophore induction of morphogenetic movement.

SEM observations reveal that papaverine, which interferes with Ca2+ flux, inhibits neural fold formation causing a flattening of the cellular surface and a broadening of cellular junctions. Ionophore A23187 and EGTA both counter this effect promoting a rapid cellular constriction which results in the formation of neural ridges and folds as individual cells become uplifted and ruffled. Flame spectrometry data indicate that as Ambystoma maculatum or mexicanum embryos neurulate Ca2+ is released to the medium, a condition which is impeded by papaverine. Ionophore A23187 induces Ca2+ influx whereas EGTA induces an efflux. Since both agents affect similar morphological changes it is suggested that the availability of free Ca2+ is crucial in controlling the morphogenetic movements of neurulation. It is now apparent that neuro-axial development in the urodele is accompanied by a Ca+2 efflux, but the mechanism(s) responsible for the ion's release is unknown.

Ambystoma↗

PubMed1985

Studies on the mechanisms of neurulation in the chick: interrelationship of contractile proteins, microfilaments, and the shape of neuroepithelial cells.

Electron microscopy and indirect immunofluorescence were employed to correlate the distribution patterns of major contractile proteins (actin and myosin) with 1) the organizational state of microfilaments, 2) the apical cell surface topography, 3) the shape of the neuroepithelial cells, and 4) the degree of bending of the neuroepithelium during neurulation in chick embryos at Hamburger and Hamilton stages 5-10 of development. Both actin and myosin are present at these developmental stages and colocalize in the neural plate as well as in later phases of neurulation. During elevation of neural folds, actin- and myosin-specific fluorescence is always most intense in regions where the greatest degree of bending of the neuroepithelium takes place [e.g., the midline of the V-shaped neuroepithelium (early neural fold stage) and the midlateral walls of the "C"-shaped neuroepithelium (mid-neural-fold stage)]. This intense fluorescence coincides with 1) a particularly dense packing of microfilaments and 2) highly constricted cell apices. After neural folds make contact, there is an overall reduction in both the intensity of apical fluorescence and the thickness of apical microfilament bundles, especially in the roof and floor of the neural tube. The remaining fluorescence in the contact area is apparently related to cellular movements during fusion of neural folds.

Actin Cytoskeleton↗

PubMed1994

Methanol-induced neural tube defects in mice: pathogenesis during neurulation.

A spectrum of cephalic neural tube defects was observed in near-term (gestation day [GD] 17) mouse fetuses following maternal inhalation of methanol at a high concentration (15,000 ppm) for 6 hr/day during neurulation (GD 7-9). Dysraphism, chiefly exencephaly, occurred in 15% of fetuses, usually in association with reduction or absence of multiple bones in the craniofacial skeleton and ocular anomalies (prematurely open eyelids, cataracts, retinal folds). Measurements of cerebrocortical width in grossly normal, methanol-exposed fetuses revealed significant semiquantitative differences in the thicknesses of the frontal cortex and its constituent layers (neuroepithelium, intermediate cortex/subventricular plate, and cortical layer 1) as well as apparent increases in subventricular plate cellularity relative to controls. Subsequently, the early morphogenesis of these neural changes was investigated in neurulating mouse embryos to define tissue-specific patterns of methanol-induced damage that lead to cephalic axial dysraphism. Following daily 6-hr maternal inhalations of 15,000 ppm methanol during GD 7-8, the cephalic neural fold margins were swollen, blunted, and poorly elevated on GD 8.5 and 9 relative to controls. Histopathology of exposed GD 8.5 embryos revealed microcephaly in association with reductions in the cell density and mitotic index of at least 47% in the cranial mesoderm. The mitotic index in the embryonic neuroepithelium was also reduced by 55%, and groups of neural crest cells were displaced to the neural folds dorsal to the foregut (relative to the more ventral location in the facial regions of control embryos). When examined on GD 9.5 and 10.5, maternal methanol exposure (15,000 ppm for 6 hr/day) during GD 7-9 resulted in stunting, delayed rotation, and microcephaly in over 90% of the affected embryos. Persistent patency of the anterior neuropore and prosencephalic hypoplasia were seen in > 40% and up to 90% of embryos, respectively. Shallow optic vesicles, stunted branchial arches, scoliosis, and hydropericardium were also observed. Many 10.5-day-old embryos were edematous. Occult dysraphism, recognized grossly by abnormally narrow cephalic conformation and histopathologically by the absence of mesoderm in the mesencephalon, was present in at least 21% of methanol-exposed embryos on GD 9.5 and 10.5. Nile blue vital dye staining of methanol-exposed embryos revealed no difference in dye accumulation between control and treated embryos on GD 8.5, 9.0, or 9.5. There were no apparent dysmorphogenic effects in control embryos at any stage of development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

The distribution of cell surface glycoconjugates during mouse secondary neurulation.

During secondary neurulation in the mouse, the neural tube develops from the tail bud by caudal extension of the primary neurocoele. The mesenchymal cells of the tail bud become radially arranged around the neurocoele and undergo a mesenchymal to epithelial transformation to form a neuroepithelium. In order to study the expression of glycoconjugates during the morphogenesis of the secondary neural tube, 14 lectins were applied to serial sections of tail buds at various stages of development. In general, binding was fairly homogeneous during the early stages of tail bud development. However, as development progressed, several lectins became localized to specific structures. The changes were observed to parallel the ongoing development of the secondary neuraxis. sWGA, which is N-acetylglucosamine (GlcNAc) specific, bound mainly to the luminal surface of the secondary neurocoele and to a lesser extent, the notochord. WGA, which has both GlcNAc and sialic acid specificities, showed most intense binding at the luminal and abluminal surfaces of the secondary neurocoele. Binding by the lectin PNA was restricted to the extracellular matrix around the developing secondary neural tube. A comparison of the lectin binding patterns in mouse with those previously reported in chick, demonstrates a less elaborate pattern of lectin binding in murine embryos. This may suggest a less complex expression of glycoconjugates in rodents, in keeping with their comparatively simpler mechanism of secondary neurulation.

Animals↗

PubMed1987

The development of the human brain, the closure of the caudal neuropore, and the beginning of secondary neurulation at stage 12.

Twenty-four embryos of stage 12 (26 days) were studied in detail and graphic reconstructions of five of them were prepared. The characteristic features of this stage are 21-29 pairs of somites, incipient or complete closure of the caudal neuropore, and the appearance of upper limb buds. The caudal neuropore closes during stage 12, generally when 25 somitic pairs are present. The site of final closure is at the level of future somite 31, which corresponds to the second sacral vertebral level. Non-closure of the neuropore may be important in the genesis of spina bifida aperta at low levels. The primitive streak probably persists until the caudal neuropore closes, when it is replaced by the caudal eminence or end-bud (Endwulst oder Rumpfknospe). The caudal eminence, which appears at stage 9, gives rise inter alia to hindgut, notochord, caudal somites, and the neural cord. The material for somites 30-34 (which appear in stage 13) is laid down during stage 12, and its absence would be expected to result in sacral agenesis. Aplasia of the caudal eminence results in cloacal deficiency and various degrees of symmelia. The junction of primary and secondary development (primäre und sekundäre Körperentwicklung) is probably at the site of final closure of the caudal neuropore. Secondary neurulation begins during stage 12. The cavity of the already formed spinal cord extends into the neural cord, and isolated spaces are not found within the neural cord. Primary and secondary neurulation are probably coextensive with primary and secondary development of the body, respectively. The telencephalon medium has enlarged, two mesencephalic segments (M1 and M2) are distinguishable, and rhombomere 4 is reduced. The sulcus limitans is detectable in the spinal cord and hindbrain (RhD), and in the mesencephalon and diencephalon, where it extends as far rostrally as the optic sulcus in D1. A marginal layer is appearing in the rhombencephalon and mesencephalon. The first nerve fibres are differentiating, chiefly within the hindbrain (from the nucleus of the lateral longitudinal tract). Optic neural crest is at its maximum, and the otic vesicle is giving crest cells to ganglion 7/8. Neural crest continues to develop in the brain and contributes to cranial ganglia 5, 7/8, and 10/11. The spinal crest extends as far caudally as somites 18-19 but shows no subdivision into ganglia yet. Placodal contribution to the trigeminal ganglion is not certain at stage 12. Such a contribution to ganglion 7/8 is not unlikely.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain↗

PubMed1989

Heparitinase treatment of rat embryos during cranial neurulation.

Heparan sulphate has been reported to be present in rat embryos. It is covalently linked to a core protein as heparan sulphate proteoglycan (HSPG). Heparitinase specifically degrades heparan sulphate, thus treatment of rat embryos with this enzyme in vitro should result in the perturbation of any tissue interactions which involve heparan sulphate proteoglycan. In this study heparitinase was either added to the culture medium or microinjected directly into the amniotic cavity. Heparitinase treatment resulted in abnormal development of the whole embryo, but the earliest effects were observed in the cranial region. Forebrain development was grossly abnormal: the neural folds remained widely open, with beak-like outgrowths rostrally. Optic sulci failed to develop. The midbrain and rostral hindbrain neural folds also remained widely open. In the trunk, where the pattern of neurulation is less complex than in the cranial region, rostral neural tube closure did occur although the morphology of the closed region was far from normal. These results suggest that heparan sulphate proteoglycan is essential for normal neurulation. Epithelial somite formation was perturbed, but neural crest cell emigration, otic pit formation and pharyngeal arch formation, all important morphogenetic events which occur during this period of development, were not inhibited by heparitinase treatment. Prolonged (44 h) exposure to the enzyme resulted in the conversion of the embryonic structure to a much simpler form: mesenchymal cells (stellate or spindle-shaped) enclosed within a simple epithelial coating.

Animals↗

PubMed1996

Diabetes mellitus affects prostaglandin E2 levels in mouse embryos during neurulation.

The arachidonic acid cascade leading to prostaglandins has been implicated in diabetic embryopathy. Both arachidonic acid and prostaglandin E2 reverse the teratogenic effects of high glucose concentrations on neural tube development in mouse embryos in culture. Arachidonic acid supplementation also protects against diabetes-induced neural tube defects in vivo. In the present study, prostaglandin E2 was measured directly in embryos from normal and diabetic mice. In normal mice a clear developmental pattern was seen. Prostaglandin E2 levels were high during early formation of the cranial neural folds (day 8), declined during convergence and fusion of the cranial neural folds to form the neural tube (day 9), and were low after neurulation was complete (days 10 and 11). In addition, evidence in this study indicates that embryos have cyclooxygenase activity capable of generating prostaglandin E2 during a brief developmental period preceding neural tube closure. In embryos from mice made diabetic (> 13.9 mmol/l glucose) with streptozotocin, prostaglandin E2 levels were significantly lower than normal during early development of the cranial neural folds (day 8), but similar to normal after the cranial neural tube had closed (late day 9 and day 10). The findings suggest that diabetes mellitus, as ascertained by high blood glucose, promotes cranial neural tube malformations by causing a functional deficiency of prostaglandin E2 during early neurulation. Whether the altered PGE2 pattern in the embryo indicates a diabetic effect on the arachidonic acid-prostaglandin cascade in cells of the embryo or in cells of extraembryonic or maternal tissues is uncertain.

Animals↗

PubMed1988

Glycosaminoglycans vary in accumulation along the neuraxis during spinal neurulation in the mouse embryo.

We have utilized the method of whole embryo culture for metabolic labeling of mouse embryos with [3H]glucosamine during closure of neural folds at the posterior neuropore (27- to 29-somite stage). Accumulations of newly synthesized glycopeptides, lactosaminoglycans, hyaluronate, and sulfated glycosaminoglycans (GAG) were assessed by ion-exchange chromatography of glycoconjugates isolated from labeled embryos. Accumulation of hyaluronate and sulfated GAG was greatest in the posterior neuropore and decreased progressively toward the hindbrain where neurulation was already complete. Hyaluronate comprised a progressively smaller proportion of total newly synthesized glycoconjugate from the posterior neuropore toward the cranial region and glycopeptides showed the opposite trend. Sulfated GAG and lactosaminoglycans showed no consistent differences in relative abundance along the neuraxis. Autoradiographic analysis of newly synthesized glycoconjugates revealed especially heavy incorporation into developing basement membranes, beneath the neuroepithelium and around the notochord, in the posterior neuropore and recently closed neural tube regions, but not at more cranial levels of the neuraxis. Predigestion of sections with a specific hyaluronidase showed a significant quantity of this glycoconjugate to be hyaluronate. These results are consistent with a role for neuroepithelial and notochordal basement membrane hyaluronate in spinal neurulation.

Animals↗

PubMed2006

Quantitative analysis of s-adenosylmethionine and s-adenosylhomocysteine in neurulation-stage mouse embryos by liquid chromatography tandem mass spectrometry.

The potential importance of the methylation cycle during embryonic development necessitates the establishment of methodology to detect alterations in the relative abundance of s-adenosylmethionine (SAM) and s-adenosylhomocysteine (SAH) in an embryonic experimental system. We have developed a precise and sensitive method for measurement of SAM and SAH based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in single neurulation-stage mouse embryos. Use of a penta-fluorinated high-performance liquid chromatography (HPLC) stationary phase gave enhanced sensitivity due to optimal ionisation in organic mobile phase and increased retention time compared to standard reversed-phase separation. Calibration curves suitable for the analysis of neurulation-stage mouse embryos (SAM 0.02-25.0microM, SAH 0.01-10.0microM) were linear (r(2)>0.997) with limits of detection for SAM and SAH of 10 and 2.5nmol/L, respectively.

Animals↗

PubMed2005

15-zinc finger protein Bloody Fingers is required for zebrafish morphogenetic movements during neurulation.

A novel zebrafish gene bloody fingers (blf) encoding a 478 amino acid protein containing fifteen C(2)H(2) type zinc fingers was identified by expression screening. As determined by in situ hybridization, blf RNA displays strong ubiquitous early zygotic expression, while during late gastrulation and early somitogenesis, blf expression becomes transiently restricted to the posterior dorsal and lateral mesoderm. During later somitogenesis, blf expression appears only in hematopoietic cells. It is completely eliminated in cloche, moonshine but not in vlad tepes (gata1) mutant embryos. Morpholino (MO) knockdown of the Blf protein results in the defects of morphogenetic movements. Blf-MO-injected embryos (morphants) display shortened and widened axial tissues due to defective convergent extension. Unlike other convergent extension mutants, blf morphants display a split neural tube, resulting in a phenotype similar to the human open neural tube defect spina bifida. In addition, dorsal ectodermal cells delaminate in blf morphants during late somitogenesis. We propose a model explaining the role of blf in convergent extension and neurulation. We conclude that blf plays an important role in regulating morphogenetic movements during gastrulation and neurulation while its role in hematopoiesis may be redundant.

Amino Acid Sequence↗

PubMed2006

The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms.

Here we characterize the consequences of elevated bone morphogenetic protein (BMP) signaling on neural tube morphogenesis by analyzing mice lacking the BMP antagonist, Noggin. Noggin is expressed dorsally in the closing neural folds and ventrally in the notochord and somites. All Noggin-/- pups are born with lumbar spina bifida; depending on genetic background, they may also have exencephaly. The exencephaly is due to a primary failure of neurulation, resulting from a lack of mid/hindbrain dorsolateral hinge point (DLHP) formation. Thus, as previously shown for Shh signaling at spinal levels, BMP activity may inhibit cranial DLHP morphogenesis. However, the increased BMP signaling observed in the Noggin-/- dorsal neural tube is not sufficient to cause exencephaly; it appears to also depend on the action of a genetic modifier, which may act to increase dorsal Shh signaling. The spinal neural tube defect results from a different mechanism: increased BMP signaling in the mesoderm between the limb buds leads to abnormal somite differentiation and axial skeletal malformation. The resulting lack of mechanical support for the neural tube causes spina bifida. We show that this defect is due to elevated BMP4 signaling. Thus, Noggin is required for mammalian neurulation in two contexts, dependent on position along the rostrocaudal axis.

Animals↗

PubMed2003

Neural differentiation of caudal cell mass (secondary neurulation) in chick embryos: Hamburger and Hamilton Stages 16-45.

In an attempt to understand the events in the secondary neurulation in embryonic stage, we investigated morphological changes in the tail bud of normal developing chick embryos. Hamburger and Hamilton stage 16-45 embryos were harvested and processed for light microscopic studies. The secondary neural tube is formed by aggregation of the caudal cell mass. Cells are arranged into a cord-like mass (medullary cord), which is continuous with the primary neural tube. Multiple small cavities develop in the medullary cord, and these cavities coalesce into one single lumen. The process of coalescence is completed by stage 35, and the whole neural tube is transformed into one tube with a single continuous lumen. At this stage, the terminal portion of the neural tube is bulged dorsally. Thereafter, the caudal portion of the neural tube regresses, and the proximal portion develops into normal spinal cord. Transient occlusion of the central canal was observed at stage 40 in one sample. The sequence of events elucidated in this study can be used as base-line data for experiments concerning congenital malformations involving secondary neurulation.

Animals↗

PubMed2001

Is the re-closure of surgically induced open neural tube defect the repetition of primary neurulation? An experimental study with chick embryos.

It is well known that surgically induced open neural tube defects (ONTDs) tend to re-close in early embryonic stages. To investigate whether the process of re-closure is a repetition of primary neurulation, the morphological changes of surgically induced ONTDs were chronologically examined in early chick embryos. Longitudinal incisions of 3-somite length were made in the neural tubes of chick embryos at Hamburger and Hamilton stage 18 or 19. About half of the embryos showed complete closure of the skin on surgical microscopic examination. The re-closed neural tubes showed no remarkable differences from the controls on histological examination. The process of re-closure involved a zipper-like (ventral to dorsal) closure in the transverse sections of neural tubes. The results indicate that the re-closure of surgically induced ONTDs does not repeat the process of natural primary neurulation.

Age Factors↗

PubMedDate not supplied

Dysmorphogenic effects of a specific protein kinase C inhibitor during neurulation.

Protein kinase C (PKC) plays a key role in signal transduction and is an important mediator of events throughout development. However, no information exists regarding the effect of a specific PKC inhibitor on mammalian embryogenesis during neurulation. This investigation was undertaken to examine the effects of a specific inhibitor of PKC, as well as inhibitors of other important kinases, on cultured mouse embryos. CD-1 mouse embryos (3 to 6 somite stage) were exposed to bisindolylmaleimide I (a specific PKC inhibitor) as well as specific inhibitors of PKA, PKG, and MAP kinase kinase for 24 h. The PKC inhibitor was a potent embryotoxicant and elicited malformations at concentrations as low as 0.01 microM. Inhibitors of other kinases also produced malformations but at much higher concentrations than those required to produce similar defects with the PKC inhibitor. These data suggest that PKC plays an important role in mammalian neurulation. Further research is required to clarify the mechanism by which PKC inhibition at this developmental stage produces malformations and the potential effects of environmental toxicants with PKC inhibitory properties on this signal transduction pathway.

Alkaloids↗

PubMed1998

Essential roles for the Abl and Arg tyrosine kinases in neurulation.

The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system. Arg is most abundant in adult mouse brain, especially in synapse-rich regions. arg(-/-) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg(-/-) brains suffer from defects in neuronal function. Embryos deficient in both Abl and Arg suffer from defects in neurulation and die before 11 days postcoitum (dpc). Although they divide normally, abl(-/-)arg(-/-) neuroepithelial cells display gross alterations in their actin cytoskeleton. We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium. Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton.

Actins↗

PubMed2000

Control of neurulation by the nucleosome assembly protein-1-like 2.

Neurulation is a complex process of histogenesis involving the precise temporal and spatial organization of gene expression. Genes influencing neurulation include proneural genes determining primary cell fate, neurogenic genes involved in lateral inhibition pathways and genes controlling the frequency of mitotic events. This is reflected in the aetiology and genetics of human and mouse neural tube defects, which are of both multifactorial and multigenic origin. The X-linked gene Nap1l2, specifically expressed in neurons, encodes a protein that is highly similar to the nucleosome assembly (NAP) and SET proteins. We inactivated Nap1l2 in mice by gene targeting, leading to embryonic lethality from mid-gestation onwards. Surviving mutant chimaeric embryos showed extensive surface ectoderm defects as well as the presence of open neural tubes and exposed brains similar to those observed in human spina bifida and anencephaly. These defects correlated with an overproduction of neuronal precursor cells. Protein expression studies showed that the Nap1l2 protein binds to condensing chromatin during S phase and in apoptotic cells, but remained cytoplasmic during G1 phase. Nap1l2 therefore likely represents a class of tissue-specific factors interacting with chromatin to regulate neuronal cell proliferation.

Animals↗

PubMed2003

The genetic basis of mammalian neurulation.

More than 80 mutant mouse genes disrupt neurulation and allow an in-depth analysis of the underlying developmental mechanisms. Although many of the genetic mutants have been studied in only rudimentary detail, several molecular pathways can already be identified as crucial for normal neurulation. These include the planar cell-polarity pathway, which is required for the initiation of neural tube closure, and the sonic hedgehog signalling pathway that regulates neural plate bending. Mutant mice also offer an opportunity to unravel the mechanisms by which folic acid prevents neural tube defects, and to develop new therapies for folate-resistant defects.

Animals↗