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PubMed1998

Nicotine evokes cell death in embryonic rat brain during neurulation.

Maternal cigarette smoking during pregnancy represents the most prevalent exposure to a suspected neuroteratogen, nicotine. Although animal models have demonstrated brain cell loss and synaptic abnormalities after prenatal nicotine exposure, the multiple effects of nicotine on the maternal-fetal unit make it difficult to prove that nicotine itself is a neuroteratogen. In the current study, whole rat embryo culture was used to study the effects of nicotine at the neural tube stage of development. Beginning on embryonic day 9.5, embryos were exposed to 1, 10 or 100 microM nicotine. After 48 hr, embryos were examined for dysmorphogenesis and were then processed for light microscopic examination of the neuroepithelium. Examination of the forebrain, midbrain and hindbrain regions revealed extensive cytotoxicity, evidenced by cytoplasmic vacuolation, enlargement of intercellular spaces and a sharply increased incidence of pyknotic/apoptotic cells. These alterations were evident in the absence of generalized dysmorphogenesis and were detectable even at the lowest concentration of nicotine. At the highest concentration, abnormalities were present in the majority of cells. Superimposed on cell damage, we found an increase in mitotic figures. Although enhanced mitosis could represent partial compensation for cell loss, the regional selectivity and concentration dependence of the mitogenic effect differed significantly from that of cell death, suggesting separable mechanisms. The present results support the view that nicotine is a neuroteratogen, specifically targeting brain development at concentrations below the threshold for dysmorphogenesis.

Animals↗
PubMed1991

Computer modelling of neural tube defects.

Neurulation, the curling of the neuroepithelium to form the neural tube, is an essential component of the development of animal embryos. Defects of neural tube formation, which occur with an overall frequency of one in 500 human births, are the cause of severe and distressing congenital abnormalities. However, despite the fact that there is increasing information from animal experiments about the mechanisms which effect neural tube formation, much less is known about the fundamental causes of neural tube defects (NTD). The use of computer models provides one way of gaining clues about the ways in which neurulation may be compromised. Here we employ one computer model to examine the robustness of different cellular mechanisms which are thought to contribute to neurulation. The model, modified from that of Odell et al (Odell, G.M., Oster, G., Alberch, P. and Burnside, B., (1981)) mimics neurulation by laterally propagating a wave of apical contraction along an active zone within a ring of cells. We link the results to experimental evidence gained from studies of embryos in which neurulation has been perturbed. The results indicate that alteration of one of the properties of non-neural tissue can delay or inhibit neurulation, supporting the idea, gained from observation of embryos bearing genes which predispose to NTD, that the tissue underlying the neuroepithelium may contribute to the elevation of the neural folds. The results also show that reduction of the contractile properties of a small proportion of the neuroepithelial cell population may have a profound effect on overall tissue profiling. The results suggest that the elevation of the neural folds, and hence successful neurulation, may be vulnerable to relatively minor deficiencies in cell properties.

Animals↗
PubMed1989

Does lumbosacral spina bifida arise by failure of neural folding or by defective canalisation?

The aim of this study was to determine whether open lumbosacral spina bifida results from an abnormality of neural folding (primary neurulation) or medullary cord canalisation (secondary neurulation). Homozygous curly tail (ct) mouse embryos were studied as a model system for human neural tube defects. The rostral end of the spina bifida was found to lie at the level of somites 27 to 32 in over 90% of affected ct/ct embryos. Indian ink marking experiments using non-mutant embryos showed that the posterior neuropore closes, and primary neurulation is completed, at the level of somites 32 to 34. Since neurulation in mammals progresses in a craniocaudal sequence, without overlap between regions of primary and secondary neurulation, we conclude that spina bifida in ct/ct embryos arises initially as a defect of primary neurulation. The position of posterior neuropore closure in human embryos is estimated to lie at the level of the future second sacral segment indicating that in humans, as in the ct mouse, lumbosacral spina bifida usually arises as a defect of posterior neuropore closure. Cranial NTD affect females predominantly, whereas lower spinal NTD are more common in males, both in humans and ct mice. We offer an explanation for this phenomenon based on (a) differences in the effect of embryonic growth retardation on the likelihood that an embryo will develop either cranial or lower spinal NTD and (b) differences in the rate of growth and development of male and female embryos at the time of neurulation.

Animals↗
PubMed1992

Evaluation of neural fold fusion and coincident initiation of spinal cord occlusion in the chick embryo.

Although it is known that rapid expansion of the vertebrate brain begins near the time that the spinal neurocoel is occluded, it still remains unknown when occlusion occurs in relation to neurulation. Since both morphogenetic events are critical for normal brain growth, it is important to decipher the temporal relationship between the two processes. This study assessed the temporal relationship of the two events with the rationale that if it could be demonstrated that occlusion occurs coincident with the completion of neurulation, then it could be argued that factors shown to direct neurulation could also initiate occlusion. Nearly 600 chick embryos (stages 9- through 12+) were cultured atop egg-agar, the caudal extent of neurulation determined, the cranial five pairs of somites removed and the neurocoels assessed for occlusion. In stage 9- through 10- chicks, neurulation of the spinal cord is incomplete. Stages 10 through 12+ exhibit neurulation and occlusion from the 8th to 19th somites. When lateral tissues were removed in embryos 8 through 10-, the neural folds became dysraphic whereas in embryos stage 10 and older, the folds remained fused dorsomedially and occluded. The only surgical manipulation that was found to prevent occlusion was elimination of the lateral tissues responsible for elevation and closure of the neural folds. Analysis of particular components of the lateral tissues essential for convergence, by treating embryos (n = 75) with chemicals known to degrade tissue-tissue bonds or specific components of the perineural matrix, indicated that more than 75% of the embryos treated with EDTA, EDTA plus Ca2+, trypsin, collagenase, or hyaluronidase exhibited little or no effect on convergence, dorsomedial fusion, and concomitant occlusion.

Animals↗
PubMedDate not supplied

[Embryonic mechanisms in development of spina bifida in humans].

The study of 86 human embryos and fetuses beginning from 23rdday of development up to 18th week after fecundation has detected 23 cases of pathologic development which correspond to the modern definition of spina bifida (SB). It is shown that the cause of various forms of the anomaly is the disturbance or temporary delay of a movement of caudal neurulation wave forming the spinal cord. The anomaly size and type are determined by the time and duration of a pathogenic action on neurulation. Postnatal or the 1st type of SB develops in neurulation wave disturbance not longer than 4-6 hours. Anomaly consequence may be compensated surgically. The 2nd or fetal type of SB arises when neurulation delay is from 6 to 20 hours. If the delay occurs on the 22-24th day of development, embryos die by the neurulation end. If the delay takes place on the 26-28th day embryos may survive till the late fetal period. In embryonal or type III of SB embryos die by the end of the 8th week and do not enter the medical statistics. Their death is associated with delayed movement of the caudal neurulation wave for 24 hours and longer. This results in a spontaneous abortion.

Gestational Age↗
PubMed1979

The function of the sodium pump during differentiation of amphibian embryonic neurones.

1. A method has been developed for studying the differentiation in tissue culture of ectoderm and mesoderm derivatives, dissected from amphibian embryos which have just completed neurulation. 2. Neurones, striated muscle cells and pigment cells, together with other unidentifiable cell types, differentiated as a monolayer with approximately the same time course as in the whole embryo. The proportion of different cell types in the cultures was measured quantitatively by cell counting. 3. Treatment of embryos during neurulation with the cardiac glycoside strophanthidin reduced the number of neurones which subsequently differentiated in culture. Other cell types were not affected. 4. The relationship between inhibition of neural differentiation and strophanthidin concentration was sigmoid, with maximum inhibition at 10(-5) M-strophanthidin and the mid-point at 5 X 10(-7) M-strophanthidin. 35% of neurones differentiating in culture were not affected by glycoside treatment. 5. The glycoside hexahydroscillaren A had no effect on neural differentiation. 6. Increasing extracellular potassium to 100 nM during strophanthidin treatment completely protected differentiating neurones from the inhibitory effect of strophanthidin. 7. Treatment of embryos with 100 mM-KCl during neurulation had no effect on the subsequent differentiation of neurones. 8. Treatment of cultures with an antibody to mouse salivary gland Nerve Growth Factor reduced the number of neurones by 30%. 9. Exposure to strophanthidin while the embryo moved from the early neural fold stage to the late neural fold stage was as effective in reducing subsequent neural differentiation as treatment throughout neurulation. 10. The proportion of nerve cells in the cultures was not affected if strophanthidin treatment ended before the early neural fold stage or did not begin until the late neural fold stage. 11. Embryos treated with strophanthidin during neurulation and then allowed to grow into tadpoles developed abnormal nervous systems. 10(-6) M-strophanthidin had little effect on the volume of grey matter, but reduced the white matter by 50%. 12. The results are consistent with the view that strophanthidin achieves its effect on neural differentiation by inhibiting the sodium pump. They are discussed in the light of the suggestion that activation of the sodium pump is an essential part of nerual differentiation.

Ambystoma↗
PubMed1982

Intracellular sodium and the differentiation of amphibian embryonic neurones.

1. Experiments have been done to examine the mechanism of the inhibition of neural differentiation produced by inhibiting the sodium pump with cardiac glycosides during the mid-neural fold stages of development of the amphibian embryo. Neural differentiation was assessed quantitatively by counting the number of neurones that undergo primary differentiation in tissue culture, as a proportion of the total number of differentiated cells.2. Inhibition of the sodium pump by lowering the extracellular potassium concentration ([K(o)]) to 0 during the mid-neural fold stages inhibited neural differentiation.3. Raising the extracellular calcium concentration to 10 mM during treatment with strophanthidin protected differentiating neurones from the effects of the sodium pump inhibitor. Lowering [Ca](o) to 0.05 mM potentiated the effect of low doses of glycoside.4. In the presence of high extracellular calcium and 5 x 10(-6) M-strophanthidin the membrane potential of neural plate cells remained close to the levels recorded at the beginning of neurulation; the normal increase in resting potential was not restored.5. Addition of 10 mM-Sr(2+) to the bathing medium also protected nerve cells against the inhibition produced by strophanthidin; Sr(2+) was less effective than Ca(2+).6. Addition of either 10 mM-Mg(2+) or Mn(2+) had no effect on the inhibition of differentiation produced by strophanthidin.7. Addition of Mn(2+) along with high Ca(2+) prevented calcium from exerting its protective effect.8. The eyes of embryos treated with high Ca(2+) together with strophanthidin during neurulation and then allowed to grow into tadpoles developed normally. When Mn(2+) was present together with Ca(2+) and strophanthidin the eyes were disrupted similarly to those of embryos treated with strophanthidin alone.9. Replacement of extracellular sodium with equimolar amounts of choline or lithium prevented the cardiac glycoside from inhibiting neural differentiaion.10. The protection afforded by lowering [Na](o) was abolished when [Ca](o) was simultaneously lowered to 0.05 mM.11. Tadpoles from embryos treated with low extracellular sodium together with strophanthidin during neurulation had normal eyes compared to those treated with strophanthidin alone.12. Measurement of the intracellular sodium concentration ([Na](i)) with sodium-sensitive micro-electrodes put [Na](i) at about 30 mM before the neural folds lift. As the sodium pump is activated (stages 14(1/2)-15)[Na](i) in the neural plate falls; by the end of the mid-neural fold stage it is less than 10 mM.13. Addition of 5 x 10(-6)M-strophanthidin to the bathing fluid before activation of the sodium pump prevented the fall in [Na](i); in embryos where [Na](i) had begun to drop strophanthidin produced a rise to about 30 mM.14. When 10 mM-calcium was present along with strophanthidin [Na](i) fell to about 17 mM during neurulation, despite inhibition of the sodium pump.15. It is concluded that it is unlikely that either abolition of the normal increase in resting potential or a fall in gap junction permeability is responsible for the reduction in neural differentiation produced by blocking the sodium pump during neurulation.16. The results are consistent with the view that strophanthidin achieves its effect by preventing the fall in [Na](i) that occurs during normal neurulation because of activation of the sodium pump. They are discussed in the light of this suggestion.

Ambystoma mexicanum↗
PubMed1996

Sequence and developmental expression of AmphiDll, an amphioxus Distal-less gene transcribed in the ectoderm, epidermis and nervous system: insights into evolution of craniate forebrain and neural crest.

The dynamic expression patterns of the single amphioxus Distal-less homolog (AmphiDll) during development are consistent with successive roles of this gene in global regionalization of the ectoderm, establishment of the dorsoventral axis, specification of migratory epidermal cells early in neurulation and the specification of forebrain. Such a multiplicity of Distal-less functions probably represents an ancestral chordate condition and, during craniate evolution, when this gene diversified into a family of six or so members, the original functions evidently tended to be parcelled out among the descendant genes. In the amphioxus gastrula, AmphiDll is expressed throughout the animal hemisphere (presumptive ectoderm), but is soon downregulated dorsally (in the presumptive neural plate). During early neurulation, AmphiDll-expressing epidermal cells flanking the neural plate extend lamellipodia, appear to migrate over it and meet mid-dorsally. Midway in neurulation, cells near the anterior end of the neural plate begin expressing AmphiDll and, as neurulation terminates, these cells are incorporated into the dorsal part of the neural tube, which forms by a curling of the neural plate. This group of AmphiDll-expressing neural cells and a second group expressing the gene a little later and even more anteriorly in the neural tube demarcate a region that comprises the anterior three/fourths of the cerebral vesicle; this region of the amphioxus neural tube, as judged by neural expression domains of craniate Distal-less-related genes, is evidently homologous to the craniate forebrain. Our results suggest that craniates evolved from an amphioxus-like creature that had the beginnings of a forebrain and possibly a precursor of neural crest - namely, the cell population leading the epidermal overgrowth of the neural plate during early neurulation.

Amino Acid Sequence↗
PubMed1990

Dysmorphogenesis elicited by microinjected acetaminophen analogs and metabolites in rat embryos cultured in vitro.

Direct additions of acetaminophen (APAP), 3,5-dimethylacetaminophen, 3-hydroxyacetaminophen or 3-methoxyacetaminophen to the medium of cultured embryos each produced an increased incidence of morphologically similar, abnormally open anterior neuropores. Approximate concentrations required to produce an equal incidence were 0.5 mM, 1.0 mM, 0.1 mM and 0.75 mM, respectively. In contrast, 2.6-dimethylacetaminophen and N-acetyl-p-benzoquinoneimine failed to produce elevated incidences of abnormal neurulation unaccompanied by marked growth retardation. However, with intra-amniotic microinjections, 3-hydroxyacetaminophen and N-acetyl-p-benzoquinoneimine were roughly equipotent for eliciting abnormal neurulation, whereas 3-methoxyacetaminophen required greater than 30-fold higher concentrations. This suggests that N-acetyl-p-benzoquinoneimine does not readily transit the visceral yolk sac and would likely not be a major factor in APAP-elicited neural tube abnormalities unless generated in target tissues. The differential effects produced by two dimethylated (2.6 and 3.5) APAP analogs further suggest that sulfhydryl oxidation is associated more closely than sulfhydryl conjugation with the neurulation defect. Intra-amniotic microinjections of large quantities (3500 ng) of 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) or APAP failed to produce the specific neurulation defect. Microinjections of 7-OH-AAF into the exocoelomic cavity effected the characteristic abnormal neurulation. Conversion by conceptal homogenates of 7-OH-AAF was roughly 7- to 8-fold more rapid than conversion of APAP to respective catechol metabolites, and specific activities in yolk sac tissues were greater than those in the embryo. Rates of conceptal conversion to the quinoneimine were approximately 2- to 3-fold lower than catechol generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗