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PubMed1992

Pathogenesis of diastematomyelia: can a surgical model in the chick embryo give some clues about the human malformation?

To reproduce diastematomyelia, a sagittal incision was carried out at the level of the rhomboidal sinus of 36- to 40-h-old chick embryos. A small piece of membrane shell, a small agar screen, or a piece of quail isochronous isotopic notochord was inserted into the gap. The embryos were killed and fixed after 9 days' incubation. Diastematomyelia was obtained in several embryos treated with interposition of a membrane screen or a piece of quail notochord. Microscopic examination revealed two hemicords, each containing its own central canal; in some cases one of the cords showed hydromyelia. Absence of the rump was seen in association with experimental diastematomyelia. The interposition of a resorbable agar screen did not succeed in reproducing diastematomyelia. The results of these surgical manipulations suggest that diastematomyelia cannot be explained by a primary disorder of neurulation. It supports the theory of noninvolution of a firm midline structure (probably the neurenteric canal, rapidly surrounded by mesodermal cells originating from the notochord), which prevents the fusion of the separated parts.

Animals↗
PubMed1987

Developmental analysis of cephalic axial dysraphic disorders in arsenic-treated hamster embryos.

Parenteral injection of pregnant golden hamsters with inorganic arsenic salts early in gestation results, by term, in markedly elevated embryonic-fetal mortality (approximately equal to 50%) and, in surviving fetuses, a high (approximately equal to 90%) incidence of cephalic axial dysraphic disorders ("neural tube defects"), particularly exencephaly/anencephaly and encephaloceles. The present investigation traces the day by day development of these embryopathic effects of arsenic in the hamster with an emphasis on the pathogenesis of cephalic axial dysraphic disorders. Pregnant golden hamsters were given an intraperitoneal injection of sodium arsenate (20 mg/kg) on the 8th day (08.00) of their 16 day gestation period. Matched control dams were injected with an equivalent volume of distilled water by the same route and at the same stage of gestation. Experimental and control dams were sacrificed beginning 24 h after treatment and at regular daily intervals thereafter until term. Embryos and fetuses delivered from sacrificed dams were examined for abnormalities both grossly and histologically. In embryos delivered earliest after treatment (24-48 h) the principal deleterious effect of arsenic observed was retarded growth (elevation, approximation, and fusion) of the cephalic neural folds. This growth retardation ranged in severity among embryos. In the most severely afflicted there was a site wherein the opposing cephalic neural folds had completely failed to appose and fuse ("closure"). This failure of closure of all four tissue components of the neural folds (surface ectoderm, paraxial mesoderm, neural crest cells, neuroectoderm) resulted in a persistent dorsal opening in the head, i.e., cranioschisis aperta. The extent and appearance of this opening varied from a small, ovoid aperture in the dorsal midbrain (mesencephalic) region of the head to a widely open cleft involving the fore and hindbrain regions as well as the midbrain region. In less severely afflicted early embryos, the cephalic neural folds had elevated and met in the dorsal midline but had only incompletely fused, i.e., cranioschisis occulta. Microscopic study of these latter embryos revealed that in the affected region(s), complete closure of the surface ectoderm component of the neural folds had taken place, but only partial closure of the mesoderm, neural crest and neuroectoderm components. The different types of cephalic axial dysraphic disorders presenting in arsenic-treated fetuses delivered at later gestational stages (predominantly exencephaly and encephaloceles) could all be traced back and related to one or the other of these early forms of disturbed neurulation.

Abnormalities, Drug-Induced↗
PubMed1978

Peculiar pattern of interkinetic nuclear migration in the newt Notophtalmus viridescens.

The distribution of mitotic figures was studied in the neuroepithelium of Notophtalmus viridescens embryos of stages 14, 16 and 18. On the average, 34% of the mitotic figures were counted near the neurocoele (here in described as zone 1), 10% were recorded in the outer portion of the epithelium (zone 3) and 56% were found between these two regions (zone 2). It is concluded that this neuroepithelium is the site of interkinetic nuclear migration although its pattern is peculiar when compared to what occurs in the chick embryo. Also, the analysis of one micron-thick serial sections showed that the neuroepithelium in Notophtalmus viridescens is pseudo-stratified throughout neurulation.

Animals↗
PubMed1977

A stereological approach to the study of neural organogenesis in Xenopus laevis.

Stereological methods are applied to the study of structural changes undergone, during neurulation, by the neuroepithelium of early embryos of Xenopus laevis. In light microscopy, we evaluate: the section area of the neuroepithelium, the nucleocytoplasmic ratio, the volume fraction of the intercellular spaces, of the nuclei and of the cytoplasm. In electron microscopy, the volumetric density and the surface ratio of mitochondria as well as the surface density of the endoplasmic reticulum are measured. Occasionally, the data found for Xenopus are compared to those found earlier in a similar study of the chicken embryo.

Animals↗
PubMed1989

Origin of the notochord in the rat embryo tail.

The origin of the notochord in the rat tail was investigated on transverse serial semi-thin and ultra-thin sections of 12- and 13-day embryo tails. It was found that the notochord develops from a mass of condensed mesenchymal cells which is located ventrally to the secondary neural tube, and which subsequently splits into a) a thin cord which becomes notochord and b) a thick portion which gives rise to the tail gut. By analogy with the secondary neurulation and the secondary gut formation, one might therefore speak of a secondary notochord formation in the tail. It occurs in close relationship with the formation of the tail gut.

Animals↗
PubMed1995

Nhlh1, a basic helix-loop-helix transcription factor, is very tightly linked to the mouse looptail (Lp) mutation.

Looptail (Lp) is a mutation on the distal portion of mouse Chromosome (Chr) 1 that affects neurulation in mouse and is phenotypically expressed by appearance of an open neural tube along the entire antero-posterior axis of the embryo (craniorachischisis). Nhlh1, a member of the basic helix-loop-helix family of transcription factors, is expressed in the developing neural tube in structures affected by the Lp mutation and has been regionally assigned to the distal part of mouse Chr 1. Using a large panel of looptail animals from an (Lp/+ x SWR/J)F1 x SWR/J segregating backcross progeny, we have determined that Nhlh1 maps very close to Lp, with no recombinant detected in 500 informative animals tested; both map within a 0.6-cM segment defined as D1Mit113/Apoa2/Fcer1 gamma-(0.4 cM)-Nhlh1/Lp-(0.2 cM)-Fcer1 alpha/D1Mit149/Spna1. Nucleotide sequencing of Nhlh1 cDNA clones from wild type (WT) and Lp/Lp embryos failed to identify sequence alterations associated with the mutant phenotype. Southern hybridization of genomic DNA from WT and Lp/Lp embryos failed to identify specific rearrangements at or near the Nhlh1 locus, and Northern RNA blotting and RT-PCR evaluation of Nhlh1 mRNA expression indicated that both the levels and types of Nhlh1 mRNAs produced in WT and Lp/Lp embryos were indistinguishable. These studies suggest that Nhlh1 and Lp are not allelic. Nevertheless, Nhlh1 is the Chr 1 marker most tightly linked to Lp identified to date and can, therefore, be used as an excellent entry probe to clone the Lp region.

Animals↗
PubMed1991

Recovery by mouse embryos following teratogenic exposure to ketosis.

Previous studies have shown that the ketone body D,L,-beta-hydroxybutyrate was teratogenic to mouse embryos exposed in culture during the period of neurulation. Inhibition of closure of the cranial and caudal neuropores was the most frequently occurring defect and these abnormalities were thought to be the forerunner of anencephaly and spina bifida, respectively. However, additional studies demonstrated that embryos could recover morphologically from these effects if the ketone body was removed from the culture medium and if the recovery period was of sufficient duration. In an attempt to define further the phenomenon responsible for this recovery and to determine the extent of the recovery process, the present study examining the cross-sectional area, cell number, and mitotic index of cranial neuroepithelial cells was conducted in mouse embryos cultured from the early somite stage under one of the following conditions: 1) control medium for 60 h; 2) medium containing 32 mmol/l D,L,-beta-hydroxybutyrate for 24 h followed by culture in control medium for an additional 36 h (recovery group); 3) medium containing 32 mmol/l D,L,-beta-hydroxybutyrate for 60 h (continuously exposed group). The results indicate that although neural tube closure occurred in the recovery group, complete recovery was limited to the ventral regions of the forebrain and that the remainder of the prosencephalon as well as the rhombencephalon failed to undergo complete catch-up growth. Thus, cell numbers in these areas were approximately 70% of control values. Therefore, while the gross anatomical disturbances produced by the ketone body may be compensated for, histological alterations in the affected tissues remain. Ultimately, these data suggest that neurological deficits may be an outcome of ketone body exposure during the early stages of embryogenesis.

3-Hydroxybutyric Acid↗
PubMed1979

Possible evidence for secondary degeneration of central nervous system in the pathogenesis of anencephaly and brain dysraphia. A study in young human fetuses.

In an attempt to help elucidate pathogenetically those human cases exemplifying secondary degeneration of the neural tube causing brain dysraphia, macroscopic and histologic observations of two young human fetuses are described. A nine-week-old anencephalic fetus exhibited an absence of spinal cord (amyelia) with retention of neural crest derivatives (dorsal root ganglion cells and thusir processes, and sympathetic ganglia) implying the presence of a neural tube in early gestation. The second, ten-week-old exencephalic case exhibited restricted brain hemorrhage and necrosis of the telencephalon and brain stem amongst otherwise normal brain and spinal cord tissue. These two young fetal cases may represent examples of a previously normal neural tube which has undergone degeneration at a stage where neural crest has already undergone differentiation, and thus distinguishes them from cases of complete dysraphism which probably results from primary degeneration during neurulation.

Anencephaly↗
PubMed1980

Copper-induced microtubule degeneration and filamentous inclusions in the neuroepithelium of the mouse embryo.

The neuroepithelium of embryos exposed either in vivo or in vitro to copper sulphate was examined by transmission electron microscopy. Exposure to copper sulphate generally resulted in failure of elevation of the neural folds, and consequent development of neural tube defects. These defects appeared to result from the failure of individual cells of the neuroepithelium to change from a low to the high columnar form necessary for normal closure to take place. Ultrastructurally, the neuroepithelial cells showed a considerable reduction in the number of microtubules present, or contained microtubular remnants. Occasionally, deposits of approximately 100A filamentous material were also observed in the middle regions of neuroepithelial cells devoid of microtubules. The overall morphology of individual cells appeared otherwise unchanged. This study supports the concept that microtubules are required for neuroepithelial cellular elongation, an essential step during the process of neurulation. It also suggests that copper, like other microtubule-active agents, may induce the production of characteristic fibrillary deposits that are also observed in a number of neuropathological conditions.

Animals↗
PubMed1982

Intrinsic and extrinsic determinants of neuronal development: relation to infantile autism.

This paper attempts to view the autistic syndrome in the context of a disorder of brain development. The authors review some of the known or suspected causes of the autistic syndrome: maternal rubella, metabolic diseases, and heredity. Some basic principles of cellular neuroanatomy and chemical neurotransmission are sketched. The stages of human brain development from neurulation through histogenesis, cell migration, and elaboration of dendritic trees and axonal projections are described. The authors conclude that there are a limited number of developmental loci that could be disrupted and lead to the autistic syndrome, and that these most probably occur in the end stages of neuronal development, after the migrating neurons have reached their final place in the brain and have begun to elaborate communicative processes. Finally, the authors speculate on how neurochemical disturbances might alter end stage neuronal differentiation leading to the pathology of infantile autism.

Autistic Disorder↗
PubMed1992

Lipid droplets of neuroepithelial cells are a major calcium storage site during neural tube formation in chick and mouse embryos.

In situ precipitation of calcium (Ca2+) with fluoride and antimonate shows that Ca(2+)-specific precipitate is localized almost exclusively within lipid droplets of neuroepithelial cells during neural tube formation in chick and mouse embryos. The density of Ca2+ precipitate within lipid droplets is generally greater in the apical ends of cells situated in regions of the neuroepithelium that are actively engaged in bending. These findings suggest that lipid droplets, in addition to providing a source of metabolic fuel for developing neuroepithelial cells, also serve as Ca(2+)-storage and -releasing sites during neurulation.

Animals↗
PubMed1980

Phospholipase C-induced neural tube defects in the mouse embryo.

Mouse embryo neurulae were exposed in vitro to phospholipase C to examine the role of carbohydrate-rich extracellular material (ECM) during neurulation. Exposure of embryos to this agent for 12 h resulted in failure of closure of the neural tube. Ultrastructural examination revealed an absence of ECM from regions of the neural tube which failed to close.

Animals↗
PubMed2000

Neural tube defects: prevention by folic acid and other vitamins.

Folic acid has been demonstrated in clinical trials to reduce significantly the recurrence (and probably occurrence) of neural tube defects (NTD). In the U.K., there has been no decline in prevalence of NTD since the publication of the findings with folic acid. This article examines a series of questions relating to the action of folic acid, with emphasis on the use of mouse models as a source of experimental information which cannot easily be obtained by direct study of humans. Several mouse genetic NTD models exhibit sensitivity to prevention by folic acid, whereas other mice which develop morphologically similar NTD are resistant. Folic acid normalises neurulation in the sensitive mouse strains, providing evidence for a direct effect on the developing embryo, not on the pregnant female: Mouse studies do not support the proposed action of folic acid in encouraging the in utero demise of affected fetuses (i.e. terathanasia). Polymorphic variants of several folate-related enzymes have been shown to influence risk of NTD in humans and an inherited abnormality of folate metabolism has been demonstrated in one mouse NTD model. However, the biochemical basis of the action of folic acid in preventing NTD remains to be determined in detail. NTD in one folate-resistant mouse strain can be prevented by myo-inositol, both in utero and in vitro, raising the possibility of a therapeutic role also in humans. Gene-gene interactions seem likely to underlie the majority of NTD, suggesting that poly-therapy involving folic acid and other agents, such as myo-inositol, may prove more effective in preventing NTD than folic acid treatment alone.

Animals↗
PubMed1997

Heat shock and the role of the HSPs during neural plate induction in early mammalian CNS and brain development.

We have investigated the early development expressional of the heat shock protein genes (hsps) and HSP synthesis and their role during neuroectoderm induction, differentiation and early CNS formation. The expression and kinetics of 90, 73/71, 47 and 27 HSPs on neuroectoderm differentiation was compared under normal and stressed conditions. The role of HSPs on neuroctoderm cell fate including thermotolerance and apoptosis using a whole in vitro embryo culture system was studied. Hsp expression appears closely linked in early mammalian development to critical differentiation and proliferation stages in early brain and heart formation. The hsps are developmentally activated around blastula stage and HSPs are constitutively expressed at high levels during neural tube closure and are heat shock responsive. Using both Northern analysis, confocal microscopy and whole mount in situ hybridisation we have identified the mRNA hsp transcripts and HSPs during organogenesis. HSPs were detected during neuroectoderm cell induction and differentiation with the hsp mRNA being tightly regulated during the cell cycle of neuroectoderm especially at early fore-, mid-, hindbrain and heart formation. The 'chaperone' functions of the HSPs are well known, recently during gastrulation the HSP47 and 27 have been shown to specifically bind and fold to nascent collagen and actin molecules respectively. This role is essential for the formation of the basement membrane, extra cellular matrix and neural crest migration during neural plate development. HSP function was observed by using anti-sense strategy, short '5 anti-sense cDNA' hsp oligonucleotides inhibited hsp expression during gastrulation in the whole embryo cultures. The developmental activation of the heat shock element (HSE) is essential to our understanding of the HSPs role in neuronal cell fate. Using specific polyclonal antibodies to HSF1 and 2 (Dr Nakai, Kyoto University) the expression of heat shock factors (HSFs) during neuroectoderm differentiation was examined. Using Western analysis, confocal microscopy and flow cytometry HSF1 and 2 were identified and studied under both normal and heat shocked conditions. During gastrulation higher levels of HSF1 and 2 were identified in the neuroectoderm layer especially in regions of the fore-, mid- and hindbrain. The heat shock response and activation of the HSPs 90, 70, 47 and 27 families have been correlated with HSF1 and 2. The HSF1 appears to be present in all early embryonic cells but appears not to bind to the HSE until early head fold stage at gastrulation when the presence of HSF2 is observed. During neuroectoderm differentiation the activation of HSF1 and 2 appears to correlate with high constitutive expression of many of the hsps specifically hsp90, 73, 71, 47 and 27 being tightly regulated by the cell cycle at neurulation.

Animals↗
PubMed2003

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects.

AIMS/HYPOTHESIS: Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. METHODS: Maternal diabetes-induced oxidative stress was blocked with alpha-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis. RESULTS: Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and alpha-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by alpha-tocopherol and GSH-ethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. CONCLUSION/INTERPRETATION: Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress.

Animals↗
PubMed2006

High glucose alters the expression of genes involved in proliferation and cell-fate specification of embryonic neural stem cells.

AIMS/HYPOTHESIS: Maternal diabetes induces neural tube defects during embryogenesis. Since the neural tube is derived from neural stem cells (NSCs), it is hypothesised that in diabetic pregnancy neural tube defects result from altered expression of developmental control genes, leading to abnormal proliferation and cell-fate choice of NSCs. MATERIALS AND METHODS: Cell viability, proliferation index and apoptosis of NSCs and differentiated cells from mice exposed to physiological or high glucose concentration medium were examined by a tetrazolium salt assay, 5-bromo-2'-deoxyuridine incorporation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling and immunocytochemistry. Expression of developmental genes, including sonic hedgehog (Shh), bone morphogenetic protein 4 (Bmp4), neurogenin 1/2 (Neurog1/2), achaete-scute complex-like 1 (Ascl1), oligodendrocyte transcription factor 1 (Olig1), oligodendrocyte lineage transcription factor 2 (Olig2), hairy and enhancer of split 1/5 (Hes1/5) and delta-like 1 (Dll1), was analysed by real-time RT-PCR. Proliferation index and neuronal specification in the forebrain of embryos at embryonic day 11.5 were examined histologically. RESULTS: High glucose decreased the proliferation of NSCs and differentiated cells. The incidence of apoptosis was increased in NSCs treated with high glucose, but not in the differentiated cells. High glucose also accelerated neuronal and glial differentiation from NSCs. The decreased proliferation index and early differentiation of neurons were evident in the telencephalon of embryos derived from diabetic mice. Exposure to high glucose altered the mRNA expression levels of Shh, Bmp4, Neurog1/2, Ascl1, Hes1, Dll1 and Olig1 in NSCs and Shh, Dll1, Neurog1/2 and Hes5 in differentiated cells. CONCLUSIONS/INTERPRETATION: The changes in proliferation and differentiation of NSCs exposed to high glucose are associated with altered expression of genes that are involved in cell-cycle progression and cell-fate specification during neurulation. These changes may form the basis for the defective neural tube patterning observed in embryos of diabetic pregnancies.

Animals↗
PubMed2005

Noggin and basic FGF were implicated in forebrain fate and caudal fate, respectively, of the neural tube-like structures emerging in mouse ES cell culture.

We developed neural tube-like structures accompanying neural crest-like cells by treating embryonic stem (ES) cells with retinoic acid. The structures contained pseudostratified Nestin+Vimentin+ neuroepithelial cells surrounded by Masson staining+ basement membrane. betaIIItubulin+Synaptophysin+ mature neurons and glial fibrillary acidic protein (GFAP)+ glial cells dispersed outside of the membrane. Addition of Noggin to the culture induced prominent proliferation of the neuroepithelial cells, leading to epithelial hyperstratification of the structures. mRNAs of transcription factors essential for forebrain development such as Emx1/2 and Pax6 were specifically expressed and Islet1+Lim1/2- motoneurons appeared by the addition of Noggin. In contrast, basic fibroblast growth factor (bFGF) promoted enlargement of central lumen and elongation of the structures. mRNAs of caudal markers, Gbx2, Cdx2 and Hoxb4/9 were expressed and Lim1/2+ spinal motoneurons appeared by the addition of bFGF. Addition of BMP-4 similarly brought about mild enlargement of central lumen of the structures. Interestingly, the addition of BMP-4 induced Slug+ neural crest-like cells surrounding the tube-like structures. mRNAs of Snail and dHand, other markers for neural crest cells, were also expressed by the addition of BMP-4. These results suggest that Noggin lead the neural-tube like structures to forebrain fate, whereas bFGF was involved in the caudalization. BMP-4 was implicated in emergence of the neural crest-like cells. Differentiation of ES cells by the present methods may mimic neurulation and subsequent neural development of early embryos, and elucidates the opposite effects of Noggin and bFGF for the neural tube development.

Animals↗