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PubMed1984

The accumulation of prominent tadpole mRNAs occurs at the beginning of neurulation in Xenopus laevis embryos.

Cloned cDNA probes have been used to measure the sizes and titers of transcripts in total RNA preparations during early development in Xenopus laevis. Of more than 20 different sequences derived from abundant and moderately abundant RNA which were present in full-grown oocytes and persisted during early development, the transcript sizes of all but 3 of these sequences were invariant. Two transcripts were of a higher molecular weight in oocytes than in embryos, but their titers in oocytes were less than 5% their titers in embryos and thus these larger maternal transcripts do not significantly contribute to embryonic, polysomal mRNA. The oocyte transcripts and the embryonic transcripts of one of these sequences are transcribed from different though cross-hybridizing genes. Cellular titers of a number of RNA sequences have also been studied and show that increases in the cellular titers of several poly(A)+RNA species are the result of de novo transcription and not simply polyadenylation. A number of sequences abundant in tadpole RNA but absent or very rare in eggs have also been examined. All of these sequences first appear in development in substantial titers in the late gastrula or early neurula, 12-15 hr after fertilization. Many other sequences already present in eggs which persist during development show an increase in titer 12-15 hr after fertilization. These data suggest that this late gastrula transcriptional event may be a major transition of gene expression that accompanies the cellular differentiation and morphogenesis that begin at this developmental time.

Animals↗
PubMed1991

Patterns of neurepithelial cell rearrangement during avian neurulation are determined prior to notochordal inductive interactions.

In the epiblast of elongating primitive-streak-stage avian embryos, MHP cells--short wedge-shaped neurepithelial cells contained within the median hinge point of the bending neural plate--arise from the midline prenodal and nodal area, whereas L cells--tall spindle-shaped neurepithelial cells constituting the lateral neural plate--arise from paired areas flanking the cranial primitive streak. These characteristic differences in neurepithelial cell shape are acquired as a result of inductive interactions with the notochord. Both MHP and L cells undergo extensive rearrangement (intercalation) during shaping and bending of the neural plate, but their pattern of rearrangement differs. MHP cells intercalate with other MHP cells and the population always spans the midline, whereas L cells intercalate with other L cells, remaining in bulk lateral to the midline. The following experiment was performed to establish whether these distinctive rearrangement patterns are determined prior to notochordal inductive interactions. Quail prospective MHP and L cells were transplanted isochronically and heterotopically to chick host blastoderms at stages prior to formation of the notochord (to wit, prospective MHP cells were transplanted into prospective L cell territory and vice versa) and the distribution, fate, and morphological characteristics of grafted cells were determined in chimeras collected 24 hr later. Our results demonstrate that heterotopic MHP and L cells do not adopt the rearrangement pattern characteristic of their new site; rather, they change their position so that grafted MHP cells intermix with MHP cells of the host and grafted L cells intermix with L cells of the host. Thus, patterns of neurepithelial cell rearrangement are determined prior to notochordal inductive interactions. When and how this determination occurs are topics for further studies.

Animals↗
PubMed1989

Abnormal neurulation induced by 7-hydroxy-2-acetylaminofluorene and acetaminophen: evidence for catechol metabolites as proximate dysmorphogens.

Direct additions to culture media of either acetaminophen (APAP) or 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) resulted in abnormal closure of the anterior neuropores of cultured rat embryos in the absence of an exogenous bioactivation system. Concentrations required to produce a 50% incidence of the defect were approximately 500 and 250 microM for APAP and 7-OH-AAF, respectively. Losses of viability were not evident at these concentrations but 7-OH-AAF elicited a somewhat greater effect on growth parameters and generalized embryotoxicity. Transplacental induction with 3-methylcholanthrene (MC) of P450IA1 in subsequently cultured rat embryos did not detectably alter the capacity of APAP or 7-OH-AAF to effect embryotoxicity or neuropore closure. However, additions to the culture medium of exogenous hepatic bioactivating systems (S9) from MC-induced vs phenobarbital (PB)-induced adult rats produced profoundly different effects on neuropore closure. Coincubation with S9 from MC-induced rats reduced the incidence of 7-OH-AAF-elicited abnormal neuropores from 45 to 19%, whereas coincubation with S9 from PB-induced rats increased the incidence to 77%. Coincubation with MC-induced S9 produced no statistically significant effect on APAP-elicited neuropore abnormalities but, with PB-induced S9, resulted in a significant increase from 60 to 86%. Additions of 3-OH-APAP (0.1-0.2 mM) but not N-acetyl-p-benzoquinoneimine (NAPQI, 0.1-0.5 mM) to the culture medium elicited the typical neuropore abnormality. Experiments with APAP and 7-OH-AAF as substrates demonstrated that embryonic enzymes catalyzed their conversion to the corresponding catechols. Considered together, the results provided evidence that embryonic conversion of APAP or 7-OH-AAF to the corresponding catechol metabolites may be instrumental in effecting the abnormal anterior neuropore closure observed after exposure of embryos to the respective parent compounds.

2-Acetylaminofluorene↗
PubMed1994

Temporal changes in intracellular free calcium levels in the developing neuroepithelium during neurulation in the chick.

Intracellular free calcium ion (Ca2+) levels of the developing chick neuroepithelium during neural tube closure (Hamburger and Hamilton stages 3-11 of embryonic development) were determined using the hydrophobic acetoxymethyl ester of the fluorescent dye fura-2 (fura-2/AM). Temporal changes in the free Ca2+ level in neuroepithelial cells are correlated with the degree of folding of the neuroepithelium. The concentration of intracellular Ca2+ in the neuroepithelium reaches its highest level when apposing neural folds are actively making contact.

Actin Cytoskeleton↗
PubMed1984

Diazepam inhibits neurulation through its action on myosin-containing microfilaments in early chick embryos.

Diazepam (Valium/Roche) inhibited the morphogenesis of explanted stage 8 chick embryos in a dose-related manner. Diazepam, at concn of 400-500 micrograms/ml, preferentially inhibited closure of the neural tube. This inhibition was accompanied by a significant reduction in myosin content of the developing neuroepithelium. Diazepam can be used as a probe to study the contributory role of myosin in cellular and morphogenetic movements.

Animals↗
PubMed2004

Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood.

The developmental neurotoxicity of chlorpyrifos (CPF) involves multiple mechanisms, thus rendering the immature brain susceptible to adverse effects over a wide window of vulnerability. Earlier work indicated that CPF exposure at the neural tube stage elicits apoptosis and disrupts mitotic patterns in the brain primordium but that rapid recovery ensues before birth. In the current study, we assessed whether defects in cholinergic synaptic activity emerge later in development. CPF was given to pregnant rats on gestational days 9-12, using regimens devoid of overt maternal or fetal toxicity. We then examined subsequent development of acetylcholine systems and compared the effects to those on general biomarkers of cell development. Choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was increased in the hippocampus and striatum in adolescence and adulthood. In contrast, hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, an index of nerve impulse activity, was markedly subnormal. Furthermore, m2-muscarinic cholinergic receptor binding was significantly reduced, instead of showing the expected compensatory upregulation for reduced neural input. CPF also elicited delayed-onset alterations in biomarkers of cell packing density, cell number, cell size and neuritic projections, involving brain regions both with and without reductions in indices of cholinergic activity. In combination with earlier results, the current findings indicate that the developing brain, and especially the hippocampus, is adversely affected by CPF regardless of whether exposure occurs early or late in brain development, and that defects emerge in adolescence or adulthood even in situations where normative values are initially restored in the immediate post-exposure period.

Acetyl Coenzyme A↗
PubMed2005

Inhibition of transmethylation disturbs neurulation in chick embryos.

Periconceptional folic acid supplementation can reduce the occurrence of neural tube defects. A low folate status will result in reduced remethylation of homocysteine (Hcy) to methionine and, subsequently, in a rise of Hcy levels. Indeed, elevated Hcy concentrations have been reported in mothers of children with neural tube defects. In our previous study, we showed that treatment of chick embryos with Hcy resulted in a delay of neural tube closure in an in vitro model. In the present study, we examined whether this effect of Hcy is due to inhibition of transmethylation via elevation of S-adenosylhomocysteine (AdoHcy). Transmethylation involves methylation of DNA, RNA and proteins by donation of a methyl group from S-adenosylmethionine (AdoMet). After application of inhibitors of S-adenosylhomocysteine hydrolase and of methionine adenosyltransferase, a delay of anterior neuropore closure, comparable to that observed after Hcy treatment, was observed. The changes in AdoMet and AdoHcy concentrations confirmed the inhibition of S-adenosylhomocysteine hydrolase or methionine adenosyltransferase, respectively, and the AdoMet/AdoHcy ratio was decreased in all cases, indicating reduced transmethylation. Moreover, the inhibition of methionine adenosyltransferase was prevented by pretreatment with methionine. This study, therefore, indicates that the Hcy-induced delay of the neural tube closure is caused by the inhibition of transmethylation via elevation of AdoHcy levels and a reduction of the AdoMet/AdoHcy ratio.

Adenosine↗
PubMed2005

Teratogenic effects of retinoic acid on neurulation in mice embryos.

Retinoic acids (RA) are natural chemicals that exert a hormone-like activity and a variety of biological effects on early development of mouse. In this study, the probable teratogenic effects of RA on CNS have been investigated in pregnant mice (n = 20) divided into four groups: (1) untreated controls, (2) controls which received a single dose of DMSO, (3) a group that received 40 mg/kg, and (4) a group that received 60 mg/kg of all-trans RA in DMSO, respectively on the eighth day of gestation. Embryos whose dams had received 40 and 60 mg/kg doses of RA, showed malformations and decreased size. At 40 mg/kg dosage level, 50% of the embryos had closed neural tubes while at 60 mg/kg dosage level the neural tube failed to close. The neuroblast mantle layers were disorganized in the 40 mg/kg and even more in the 60 mg/kg exposed group compared to the controls. In mitosis, the density of chromatin was increased in the 60 mg/kg dose group. Compared to controls the 40 and 60 mg/kg dose groups of RA treated dams decreases in the luminal longitudinal and internal measures were observed. Also the thickness of ventricular, mantle and marginal layers was smaller. Wide intercellular spaces due to the degenerated cells at high doses of RA as well as an accumulation of intercellular fluid were observed. Therefore, the wedge shape of neuroepithelium was abolished, preventing the elevation of the neural wall.

Journal Article↗
PubMed2003

Churchill, a zinc finger transcriptional activator, regulates the transition between gastrulation and neurulation.

Gastrulation generates mesoderm and endoderm from embryonic epiblast; soon after, the neural plate is established within the epiblast-both events require FGF signaling. We describe a zinc finger transcriptional activator, Churchill (ChCh), which acts as a switch between different roles of FGF. FGF induces ChCh slowly; this activates Smad-interacting-protein-1 (Sip1), which blocks further induction of the mesoderm markers brachyury and Tbx6L by FGF. ChCh is first expressed as cells stop migrating through the primitive streak, and we show that it regulates cell ingression. We propose a simple mechanism by which FGF sensitizes cells to BMP signals. These results reveal that neural induction requires cessation of mesoderm formation at the midline in addition to the decision between epidermis and neural plate.

Amino Acid Sequence↗
PubMed2000

Subtractive hybridization identifies chick-cripto, a novel EGF-CFC ortholog expressed during gastrulation, neurulation and early cardiogenesis.

EGF-CFC genes encode a novel class of extracellular, membrane-associated proteins that notably play an important role during vertebrate gastrulation. Whereas the two cysteine-rich domains that characterize these proteins, namely the extracellular EGF-like and the CFC domain, are known to be encoded by two evolutionarily conserved exons, it is generally assumed, based on weak primary sequence identity, that the remaining parts of the protein differ among vertebrates, suggesting that known members of the EGF-CFC family do not represent true orthologs. Here, by characterizing the full cDNA and genomic sequences of a new EGF-CFC gene in chick, and by comparing them with their counterparts in human (CRIPTO), mouse (cripto and cryptic), Xenopus (FRL-1) and zebrafish (one-eyed pinhead), we show that all EGF-CFC genes share an identical genomic organization over the entire coding region. Not only are the central two exons (coding for the EGF-like and CFC motifs) conserved, but also conserved are the total number of exons, their size, their intron phase and their correlation with discrete protein modules, in particular those modules that allow the EGF-CFC motif to become membrane-associated. Therefore, despite apparent divergence between their 5' and 3'-terminal exons, all known CRIPTO-related genes are structurally orthologous. We named this novel ortholog in bird, chick-cripto. We report the mRNA distribution of chick-cripto, which begins in the epiblast of the gastrula, with a pattern similar to EGF-CFC genes of other vertebrates.

Amino Acid Sequence↗
PubMed1996

xGCNF, a nuclear orphan receptor is expressed during neurulation in Xenopus laevis.

Nuclear orphan receptors are DNA binding proteins that share the domain structure of the nuclear hormone receptor superfamily, although ligands are unknown. We have identified an orphan receptor in Xenopus laevis and named it xGCNF based on its high degree of sequence homology to the previously described murine germ cell nuclear factor (mGCNF). In gel-electrophoresis mobility shift analysis experiments in vitro translated xGCNF and mGCNF proteins both bind specifically as homodimers to the same response element, a direct repeat of the half-site consensus AGGTCA with zero spacing (DRO). Transcripts of xGCNF are found in oocytes and in much smaller amounts in the testes. In developmental Northern blots and RNase protection using RNA from different embryonic stages, zygotic expression of xGCNF peaks at midneurula. From late gastrula to midneurula stages, an anterior to posterior concentration gradient of the RNA was observed in whole mount in situ analysis. This antero-posterior gradient of expression was also observed in exogastrulae, both in the ectoderm and mesoderm. In the midneurula embryo, the mRNA was predominantly found in the neural plate and neural crest. Transcription of xGCNF in animal cap explants occurred independent of mesoderm induction.

Amino Acid Sequence↗
PubMed1999

jumonji gene is essential for the neurulation and cardiac development of mouse embryos with a C3H/He background.

The recessive mutant mouse jumonji (jmj), obtained by a gene trap strategy, shows neural tube defects in approximately half of homozygous embryos with a BALB/cA and 129/Ola mixed background, but no neural tube defects with BALB/cA, C57BL/6J, and DBA/2J backgrounds. Here, we show that neural tube and cardiac defects are observed in all embryos with a C3H/HeJ background. In addition, abnormal groove formation and prominent flexure are observed on the neural plate with full penetrance, suggesting that abnormal groove formation leads to neural tube defects. We found morphogenetic abnormalities in the bulbus cordis (future outflow tract and the right ventricle) of homozygous embryo hearts. Moreover, myocytes in the ventricular trabeculae show hyperplasia with cells filling the ventricles. Together with the observation that the jmj gene is expressed in the neural epithelium of the head neural plate and in myocytes in the bulbus cordis and trabeculae, the results show that the jmj gene plays essential roles in the normal development of the neural plate, morphogenesis of bulbus cordis, and proliferation of trabecular myocytes on a C3H/He background.

Animals↗