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PubMed1997

Molecular cloning from neurulating Ambystoma mexicanum embryos of the cDNA encoding an orphan nuclear receptor (aDOR1) closely related to TR2-11.

We have isolated a cDNA encoding a novel orphan nuclear receptor, aDOR1, closely related to testicular receptor-2 (TR2) orphan receptor family members, from neurulating Ambystoma mexicanum embryos. The cDNA sequence predicts a protein primary sequence of 416 amino acids with a calculated molecular weight of 45.8 kDa. While the DNA-binding domains of aDOR1 and hTR2-11 share 96% identity, considerable divergence is observed at both extremities of the peptides. At the N-terminus, aDOR1 is 66% identical to hTR2-11 and longer by 37 amino acids. At the C-terminus, despite a greater similarity (69%), aDOR1 is much shorter than the hTR2 isoforms and seems to encode a distinct ligand-binding domain. Expression of aDOR1 was studied by the reverse transcription polymerase chain reaction assay (RT-PCR). High mRNA levels were detected during oogenesis, they remained high during the cleavage stage, and decreased at the mid-blastula transition (MBT). Transcripts increased again at the end of gastrulation, reached a peak level during neurulation, and leveled off after closure of the neural tube. In neurulas dissected along the anteroposterior axis, aDOR1 mRNA was enriched at both extremities of the embryo, while no particular distribution was favored along the dorsoventral axis. Retinoic acid (RA) treatments at the beginning of gastrulation did not affect overall mRNA levels in the neurula nor its distribution along both axes. In the adult, expression was predominant in the brain; lower levels (about 15%) were detectable in all germ layer derivatives, except muscle. These results suggest that aDOR1 may be required for the early determination events occurring during the cleavage stages of development, and may be involved in embryogenesis and in brain function.

Ambystoma↗

PubMed2002

Programmed cell death in the neurulating embryo is prevented by the chaperone heat shock cognate 70.

Neuronal cell death is a genuine developmental process, with precise regulation and defined roles. In striking contrast, characterization of cell death that occurs at early stages of neural development is very limited. We previously showed that embryonic proinsulin increases the level of the chaperone heat shock cognate 70 (Hsc70) and reduces the incidence of apoptosis in the neurulating chick embryo [de la Rosa, et al. (1998), Proc. Natl. Acad. Sci. USA, 95, 9950]. We now demonstrate that Hsc70 is directly involved in cell survival during neurulation, as specific downregulation of endogenous Hsc70 by antisense oligodeoxynucleotide interference provoked an increase in apoptosis both in vitro and in ovo. In parallel, activation of caspase-3 was increased after hsc70 antisense oligodeoxynucleotide treatment. Dead cells were located mostly in the developing nervous system, distributed in areas where the incidence of cell death was high. These areas coincided both in vivo and under different death-inducing conditions, including antisense interference and growth factor deprivation. Hsc70 immunostaining was strong in at least some areas of high cell death. Apoptotic cells within these areas presented undetectable Hsc70 levels, however, suggesting that this protein acts as an intrinsic protector of neuroepithelial and neural precursor cells.

Animals↗

PubMed2002

Avian sickle endoblast induces gastrulation or neurulation in the isolated area centralis or isolated anti-sickle region respectively.

By the quail-chicken chimera technique, we studied, in culture, the inducing effect of sickle endoblast (derived from Rauber's sickle by centripetal and cranial migration) on the isolated Rauber's sickle-free central part of the area centralis or on the isolated Rauber's sickle-free anti-sickle region from unincubated chicken blastoderms. Just as Rauber's sickle, the flat one-cell-thick sickle endoblast (Stage 2-3, Hamburger & Hamilton, 1951) induces a primitive streak (PS) and a neural plate in the area centralis. If a vitelline membrane is interposed between the sickle endoblast and the area centralis, then a small primitive streak is still induced, suggesting the effect of a diffusible factor on PS formation. In the adjacent upper layer of an isolated anti-sickle region the apposed sickle endoblast induces only a (pre)neural plate. By contrast, this (pre)neural plate inducing effect is rapidly and totally suppressed after grafting on the anti-sickle region of whole unincubated blastoderms. This suggests dominating positional information phenomena emanating from Rauber's sickle over the whole blastoderm. After grafting sickle endoblast either on the isolated area centralis or on isolated anti-sickles, no junctional endoblast and no blood islands developed. This suggests that the differentiation of Rauber's sickle material into sickle endoblast is irreversible. Our results indicate that Rauber's sickle material under the form of sickle endoblast also influences early neurulation phenomena (at distance in space and time). The present study indicates the existence of a temporo-spatially bound cascade of gastrulation and neurulation phenomena and blood island formation in the avian blastoderm, starting from Rauber's sickle, the primary major organizer with inducing, inhibiting and dominating potencies. The latter not only plays a role by secretion of signalling molecules (positional information) but it also influences development by its cell lineages (junctional endoblast and sickle endoblast).

Animals↗

PubMed1975

An ultrastructural examination of the role of cell membrane surface coat material during neurulation.

Data from neural crest cultures indicate that cell surface coat material (CSM) is directly involved in cellular migration and events surrounding differentiation. To investigate whether the CSM also has a morphogenetic role, embryos of the amphibian Ambystoma maculatum were examined ultrastructurally throughout the stages of neurulation. Segments of the neural axis were fixed in glutaraldehyde-containing Alcian blue 8GX, which reportedly enhances preservation of CSM, and were postfixed in OsO4 containing 1 percent lanthanum nitrate, which stains the CSM. The medial groove formed by the appearance of the neural ridges contains a large amount of CSM and numerous vesicles coated with lanthanum-positive material. In contrast, the lateral ridge surfaces are covered by a small amount of uniformly distributed CSM and a paucity of vesicles. As the ridges begin to fold there is a progressive increase in the amount of CSM within the presumptive neural tube region. Further convergence of the neural folds is accompanied by an increase of CSM at their leading edges. As the folds approximate each other, lanthanum-positive material physically bridges the gap. However, as the apposing tissue actually abuts to form the neural tube, no CSM is observed in the remaining interspace. The specific distribution and sequential accumulation of cell CSM during the events of neurulation strongly suggest its direct participation in the morphogenetic process.

Ambystoma↗

PubMed2005

CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L.

Chromatin remodeling complexes play critical roles in development. Here we describe a transcription factor, CECR2, which is involved in neurulation and chromatin remodeling. CECR2 shows complex alternative splicing, but all variants contain DDT and bromodomain motifs. A mutant mouse line was generated from an embryonic stem cell line containing a genetrap within Cecr2. Reporter gene expression demonstrated Cecr2 expression to be predominantly neural in the embryo. Mice homozygous for the Cecr2 genetrap-induced mutation show a high penetrance of the neural tube defect exencephaly, the human equivalent of anencephaly, in a strain-dependent fashion. Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation.

Adenosine Triphosphatases↗

PubMed2005

Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo.

Skeletal disorders and neural tube closure defects represent clinically significant human malformations. The signaling networks regulating normal skeletal patterning and neurulation are largely unknown. Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R)). Embryos homozygous for this mutation die at birth as a result of skeletal malformations and neural tube defects. Hindbrains of exencephalic MEKK4(K1361R) embryos show a striking increase in neuroepithelial cell apoptosis and a dramatic loss of phosphorylation of MKK3 and -6, mitogen-activated protein kinase kinases (MKKs) regulated by MEKK4 in the p38 pathway. Phosphorylation of MAPK-activated protein kinase 2, a p38 substrate, is also inhibited, demonstrating a loss of p38 activity in MEKK4(K1361R) embryos. In contrast, the MEK1/2-extracellular signal-regulated kinase 1 (ERK1)/ERK2 and MKK4-Jun N-terminal protein kinase pathways were unaffected. The p38 pathway has been shown to regulate the phosphorylation and expression of the small heat shock protein HSP27. Compared to the wild type, MEKK4(K1361R) fibroblasts showed significantly reduced phosphorylation of p38 and HSP27, with a corresponding heat shock-induced instability of the actin cytoskeleton. Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation.

Animals↗

PubMed1987

Vitamin A-induced suppression/enhancement of protein glycosylation and neurulation.

Glycoconjugates play major roles in many cellular functions, e.g. cell migration and cell-to-cell adherence, which are involved in neurulation. The maternal administration of vitamin A on gestation day 8.5 and 9.0 resulted in a high percentage of primary and secondary neurulation defects in gestation day 12 mouse embryos. The neuroepithelium of normal and abnormal embryos was analyzed by one- and two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis and one-dimensional Western blots using concanavalin A (Con A) and peroxidase-conjugated wheat germ agglutinin (WGA) lectins. In vitamin A abnormal embryos, WGA binding was decreased to glycoproteins with apparent molecular weights of 15,000 and 30,000 daltons on Western blots, whereas in vitamin A normal embryos, WGA binding was increased to these glycoproteins on Western blots. Computer-aided fluorescence microscopy using fluorescein isothiocyanate (FITC)-conjugated lectins on 1-micron araldite plastic sections indicated a decrease in FITC-WGA binding to the free surface of nonneurulated neuroepithelium. These results suggest: (1) vitamin A administration may have induced a suppression of WGA-binding carbohydrate residues on 15,000- and 30,000-dalton glycoproteins in abnormal embryos, and (2) modification in the type, amount, and distribution of glycoconjugates may provide a basis for the cellular mechanisms of abnormal development of the neural tube.

Animals↗

PubMed2001

Apical accumulation of MARCKS in neural plate cells during neurulation in the chick embryo.

BACKGROUND: The neural tube is formed by morphogenetic movements largely dependent on cytoskeletal dynamics. Actin and many of its associated proteins have been proposed as important mediators of neurulation. For instance, mice deficient in MARCKS, an actin cross-linking membrane-associated protein that is regulated by PKC and other kinases, present severe developmental defects, including failure of cranial neural tube closure. RESULTS: To determine the distribution of MARCKS, and its possible relationships with actin during neurulation, chick embryos were transversely sectioned and double labeled with an anti-MARCKS polyclonal antibody and phalloidin. In the neural plate, MARCKS was found ubiquitously distributed at the periphery of the cells, being conspicuously accumulated in the apical cell region, in close proximity to the apical actin meshwork. This asymmetric distribution was particularly noticeable during the bending process. After the closure of the neural tube, the apically accumulated MARCKS disappeared, and this cell region became analogous to the other peripheral cell zones in its MARCKS content. Actin did not display analogous variations, remaining highly concentrated at the cell subapical territory. The transient apical accumulation of MARCKS was found throughout the neural tube axis. The analysis of another epithelial bending movement, during the formation of the lens vesicle, revealed an identical phenomenon. CONCLUSIONS: MARCKS is transiently accumulated at the apical region of neural plate and lens placode cells during processes of bending. This asymmetric subcellular distribution of MARCKS starts before the onset of neural plate bending. These results suggest possible upstream regulatory actions of MARCKS on some functions of the actin subapical meshwork.

Actins↗

PubMed1997

Segregating expression domains of two goosecoid genes during the transition from gastrulation to neurulation in chick embryos.

We report the isolation and characterization of a chicken gene, GSX, containing a homeobox similar to that of the goosecoid gene. The structure of the GSX gene and the deduced GSX protein are highly related to the previously described goosecoid gene. The two homeodomains are 74% identical. In the first few hours of chick embryogenesis, the expression pattern of GSX is similar to GSC, in the posterior margin of the embryo and the young primitive streak. Later during gastrulation, expression of the two genes segregate. GSC is expressed in the anterior part of the primitive streak, then in the node, and finally in the pre-chordal plate. GSX is expressed in the primitive streak excluding the node, and then demarcating the early neural plate around the anterior streak and overlying the pre-chordal plate. We demonstrate that the GSX-positive part of the primitive streak induces gastrulation, while the GSC-expressing part induces neurulation. After full extension of the streak, the fate of cells now characterized by GSX is to undergo neurulation, while those expressing GSC undergo gastrulation. We discuss the effect of a duplicated basic goosecoid identity for the generation of a chordate nervous system in ontogeny and phylogeny.

Amino Acid Sequence↗

PubMed2002

Heparan sulphate proteoglycans and spinal neurulation in the mouse embryo.

Heparan sulphate proteoglycans have been implicated in the binding and presentation of several growth factors to their receptors, thereby regulating cellular growth and differentiation. To investigate the role of heparan sulphate proteoglycans in mouse spinal neurulation, we administered chlorate, a competitive inhibitor of glycosaminoglycan sulphation, to cultured E8.5 embryos. Treated embryos exhibit accelerated posterior neuropore closure, accompanied by suppression of neuroepithelial bending at the median hinge point and accentuated bending at the paired dorsolateral hinge points of the posterior neuropore. These effects appear specific, as they can be prevented by addition of heparan sulphate to the culture medium, whereas heparitinase-treated heparan sulphate and chondroitin sulphate are ineffective. Both N- and O-sulphate groups appear to be necessary for the action of heparan sulphate. In situ hybridisation analysis demonstrates a normal distribution of sonic hedgehog mRNA in chlorate-treated embryos. By contrast, patched 1 transcripts are abnormally abundant in the notochord, and diminished in the overlying neuroepithelium, suggesting that sonic hedgehog signalling from the notochord may be perturbed by inhibition of heparan sulphation. Together, these results demonstrate a regulatory role for heparan sulphate in mouse spinal neurulation.

Actins↗

PubMed1979

Embryotoxicity of arsenic acid: light and electron microscopy of its effect on neurulation-stage rat embryo.

To clarify the light and electron microscopic changes accompanying embryonic death from a lethal dose of arsenic acid, MP 1 pregnant rats were injected i.p. with 30 mg/kg arsenic acid at 1:30 p.m. on day 9 of gestation (the neurulation stage). At 4 hours after treatment, some cell necrosis occurred in the neuroectoderm and the mesoderm of the embryo. At six hours later, cell necrosis increased in the neuroectoderm and the mesoderm, whereas those in the surface ectoderm and the endoderm were very few. In the embryo 12 hours after treatment, abnormal mitotic cells exhibiting vesiculation of the endoplasmic reticula, and abnormal interphase cells characterized by the ring-shaped nucleoli in the nucleus and the enlargement of cisternae of the endoplasmic reticula and the nuclear envelope, were observed in the neuroectoderm and the mesoderm. Debris from cell necrosis and the said abnormal mitotic and interphase cells were ejected from the neuroectoderm into the amniotic coele. In the embryo 24 hours later, neurulation was stopped and the V-shaped neural fold remained. The somite formation was retarded. The surviving cells in the embryo sometimes contained phagocytic vesicles in the cytoplasm, but no other anomalies were encountered. It was considered that a variety of metabolic reactions may be disturbed by arsenic acid, resulting in numerous cell necrosis and abnormal mitotic and interphase cells in the neuroectoderm and the mesoderm of the rat embryo.

Animals↗

PubMed1989

Lack of teratogenic effect of brief maternal insulin-induced hypoglycemia in rats during late neurulation.

We have previously shown that 1 h of maternal insulin-induced hypoglycemia is teratogenic to rat embryos during the initial stages of neurulation, when they are dependent on uninterrupted glycolysis (day 9.5-9.7 of development). To determine whether this vulnerability persists in later stages of neural tube and cardiac development, we infused insulin into 16 conscious pregnant rats for 1 h beginning after embryos had developed the capacity for aerobic glucose metabolism (day 10.6 of development). Half of the pregnant animals were allowed to become hypoglycemic (44 +/- 2 mg/dl) during the insulin infusions. The other half received glucose infusions to maintain normoglycemia (130 +/- 3 mg/dl). Normal plasma glucose levels were maintained in all animals after the insulin infusions. Embryos were examined on day 11.5 of development. At that time, 1 of 111 embryos from the normoglycemic group and 1 of 109 embryos from the hypoglycemic group were grossly malformed (P greater than .5). Means of embryo crown-rump length (4.15 +/- 0.03 vs. 4.14 +/- 0.03 mm), somite number (29.7 +/- 0.1 vs. 29.8 +/- 0.2), and total protein content (320 +/- 5 vs. 326 +/- 6 micrograms) were also similar in the two groups (P greater than .5). Thus, we could not detect an embryotoxic effect of 1 h of maternal insulin-induced hypoglycemia beginning at day 10.6 of development. This finding is in contrast to our prior demonstration that a similar period of hypoglycemia occurring earlier in neurulation (day 9.7) caused growth retardation and developmental anomalies in embryos.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

PubMed2002

Genetic basis of neural tube defects. I. Regulatory genes for the neurulation process.

Neural tube defects (NTD) together with cardiovascular system defects are the most common malformations in the Polish population (2.05-2.68/1000 newborns). They arise during early embryogenesis and are caused by an improper neural groove closure during the neurulation process. NTD can arise from the influence of specific environmental factors on the foetus. The genetic factor is also very important, because NTDs have multigenetic conditioning. It was suggested that genes connected with the regulation of neurulation could also be involved in NTD aetiology, especially when their deletion or modification leads to neural tube defects in the mouse model. Examples are genes from the PAX family, T (Brachyury), BRCA1 and PDGFRA genes.

Animals↗

PubMedDate not supplied

[The morphogenesis of the human brain on the 27th-35th day of development with disordered neurulation].

Human embryos with anomalies of brain and spinal cord were studied on 27-35th day of the development. It was established that developmental anomalies were associated with the disturbed formation of neural tube. The reconstruction of three-dimensional brain arrangement of embryos has shown the presence of different variants of nonclosed medullar tori. In mild disturbance of neurulation, there is an acceleration of organogenesis and morphological differentiation induced by the shackening of normal mechanical tensions and relaxation of neuroepithelial layers. In presence of substantial parts of open neural tube, the development of brain and ectodermal derivatives becomes disturbed to be a possible cause of anencephaly and hypotelorism. The type of disturbed neurulation inducing developmental anomalies of nervous system is suggested to be a factor which determines forms of secondary craniofacial and cranial pathology.

Abortion, Spontaneous↗

PubMed1990

Vimentin and keratin are expressed in the neurogenic tissue of the rabbit embryo during primary neurulation.

Against the commonly held belief that differential expression of keratins is a sign of neurogenic commitment amongst ectodermal cells of the early vertebrate embryo we show here that the same keratins (8 and 18) are expressed in the epidermal ectoderm and the neurectoderm throughout primary neurulation of the early rabbit embryo, i.e. between 8.5 and 11 days post conceptionem (d.p.c.). However, keratin expression decreases during this developmental period and, by the time primary neurulation is completed, keratin expression is virtually absent in the cells of the neural tube. Vimentin expression is weak, at first, but increases in a reciprocal manner as compared to the decreasing keratin expression until it has reached a high and stable level of expression in the established neural tube of the 10 to 11 day old rabbit embryo.

Animals↗

PubMed1991

Cell movements driving neurulation in avian embryos.

Neurulation, formation of the neural tube, a crucial event of early embryogenesis, is believed to be driven by the coordination of a number of diverse morphogenetic cell behaviors. Such behaviors include changes in cell number (division, death), cell shape and size (wedging, palisading and spreading), cell position (rearrangement or intercalation) and cell-cell and cell-matrix associations (including inductive interactions). The focus of this essay is on epiblast cell movements and their role in shaping and bending of the neural plate. Neurulation is a multifactorial process requiring both intrinsic (within the neural plate) and extrinsic (outside the neural plate) forces. The origin and movements of three populations of epiblast cells have been studied in avian embryos by constructing quail/chick transplantation chimeras and by labeling cells in situ with identifiable, heritable markers. MHP (median hinge-point neurepithelial) cells originate principally from a midline epiblast area rostral to and overlapping Hensen's node. In addition, a few caudal MHP cells originate from paranodal epiblast areas. MHP cells stream down the length of the midline neuraxis in the wake of the regressing Hensen's node. This streaming occurs as a result of cell division (presumably oriented so that daughter cells are placed into the longitudinal plane rather than into the transverse plane) and rearrangement (intercalation), resulting in a narrowing of the width of the MHP region with a concomitant increase in its length. L (lateral neurepithelial) cells originate from paired epiblast areas flanking the rostral portion of the primitive streak, and they stream down the length of the lateral neuraxis concomitant with regression of Hensen's node.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Primary neurulation in teleosts--evidence for epithelial genesis of central nervous tissue as in other vertebrates.

Early teleostian embryos were studied by scanning electron microscopy. Transversal and longitudinal views of the neural anlage clearly demonstrate that it has an ordinary epithelial organization consisting of parallel columnar cells. Unless it has been supposed earlier, there is no solid thickened neural plate but the neural ectoderm is tightly folded forming a very narrow neural groove. Thus, primary neurulation in teleosts is shown to occur similar to that in other vertebrates viz. by folding of the neural plate to get the neural tube. That means that the neuroepithelial cells retain their polarity instead to become organized from a randomly oriented mass of unpolarized cells, as it is thought to occur in secondary neurulation.

Animals↗

PubMedDate not supplied

[Movements of cellular material of the dorsal wall in clawed-toad embryos during gastrulation and neurulation].

The pieces of dorsal ectoderm of the Rana temporaria embryos at the early and midgastrula stages were transplated onto the dorsal surface of the X. laevis embryos of the same age and the movements and changes in the form and area of the transplants were followed from early gastrula to neurula. During the first period (early--midgastrula) all movements of the transplants were directed towards the blastopore and related ma- In the beginning of the second period the transplants moved toward the blastopore only in the most caudal region, whereas in all other regions the material was markedly displaced craniad. Until the early neurula stage these movements were related to the longitudinal expansion of the material in the dorsal area and later, during neurulation, to its transverse compression. The head region material was first markedly expanded in the transverse direction and then also contracted. Alternation of active contractions and expansion of the suprablastopore material has been revealed and mediocaudal (gastrulation) vs. craniopetal (neurulation) cell movements were distinctly shown.

Animals↗