The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Andrew J Copp - One of the best experts on this subject based on the ideXlab platform.
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Neural Tube closure cellular molecular and biomechanical mechanisms
Development, 2017Co-Authors: Evanthia Nikolopoulou, Nicholas D E Greene, Gabriel L Galea, Ana Rolo, Andrew J CoppAbstract:Neural Tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations – ‘Neural Tube defects’ – that result when closure fails. The process of Neural Tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into Neural Tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in Neural Tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field.
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Neural Tube defects
Annual Review of Neuroscience, 2014Co-Authors: Nicholas D E Greene, Andrew J CoppAbstract:Neural Tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the Neural Tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying Neural Tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.
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eLS - Neural Tube Defects
Annual Review of Neuroscience, 2014Co-Authors: Nicholas D E Greene, Andrew J CoppAbstract:Neural Tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the Neural Tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying Neural Tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.
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Neural Tube defects recent advances unsolved questions and controversies
Lancet Neurology, 2013Co-Authors: Andrew J Copp, Philip Stanier, Nicholas D E GreeneAbstract:Summary Neural Tube defects are severe congenital malformations affecting around one in every 1000 pregnancies. An innovation in clinical management has come from the finding that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention with folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in the UK. Genetic predisposition accounts for most of the risk of Neural Tube defects, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human Neural Tube closure events remains controversial, but studies of mouse models of Neural Tube defects show that anencephaly, open spina bifida, and craniorachischisis result from failure of primary neurulation, whereas skin-covered spinal dysraphism results from defective secondary neurulation. Other malformations, such as encephalocele, are likely to be postneurulation disorders.
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genetics and development of Neural Tube defects
The Journal of Pathology, 2010Co-Authors: Andrew J Copp, Nicholas D E GreeneAbstract:Congenital defects of Neural Tube closure (Neural Tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (eg anencephaly, spina bifida) varying depending on the region of Neural Tube that remains open. While mutation of > 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasizes the importance of gene-gene and gene-environment interactions in the origins of these defects. A number of cell biological functions are essential for Neural Tube closure, with defects of the cytoskeleton, cell cycle and molecular regulation of cell viability prominent among the mouse NTD mutants. Many transcriptional regulators and proteins that affect chromatin structure are also required for Neural Tube closure, although the downstream molecular pathways regulated by these proteins is unknown. Some key signalling pathways for NTDs have been identified: over-activation of sonic hedgehog signalling and loss of function in the planar cell polarity (non-canonical Wnt) pathway are potent causes of NTD, with requirements also for retinoid and inositol signalling. Folic acid supplementation is an effective method for primary prevention of a proportion of NTDs in both humans and mice, although the embryonic mechanism of folate action remains unclear. Folic acid-resistant cases can be prevented by inositol supplementation in mice, raising the possibility that this could lead to an additional preventive strategy for human NTDs in future.
Nicholas D E Greene - One of the best experts on this subject based on the ideXlab platform.
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Neural Tube closure cellular molecular and biomechanical mechanisms
Development, 2017Co-Authors: Evanthia Nikolopoulou, Nicholas D E Greene, Gabriel L Galea, Ana Rolo, Andrew J CoppAbstract:Neural Tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations – ‘Neural Tube defects’ – that result when closure fails. The process of Neural Tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into Neural Tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in Neural Tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field.
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Neural Tube defects
Annual Review of Neuroscience, 2014Co-Authors: Nicholas D E Greene, Andrew J CoppAbstract:Neural Tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the Neural Tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying Neural Tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.
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eLS - Neural Tube Defects
Annual Review of Neuroscience, 2014Co-Authors: Nicholas D E Greene, Andrew J CoppAbstract:Neural Tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the Neural Tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying Neural Tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.
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Neural Tube defects recent advances unsolved questions and controversies
Lancet Neurology, 2013Co-Authors: Andrew J Copp, Philip Stanier, Nicholas D E GreeneAbstract:Summary Neural Tube defects are severe congenital malformations affecting around one in every 1000 pregnancies. An innovation in clinical management has come from the finding that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention with folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in the UK. Genetic predisposition accounts for most of the risk of Neural Tube defects, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human Neural Tube closure events remains controversial, but studies of mouse models of Neural Tube defects show that anencephaly, open spina bifida, and craniorachischisis result from failure of primary neurulation, whereas skin-covered spinal dysraphism results from defective secondary neurulation. Other malformations, such as encephalocele, are likely to be postneurulation disorders.
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genetics and development of Neural Tube defects
The Journal of Pathology, 2010Co-Authors: Andrew J Copp, Nicholas D E GreeneAbstract:Congenital defects of Neural Tube closure (Neural Tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (eg anencephaly, spina bifida) varying depending on the region of Neural Tube that remains open. While mutation of > 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasizes the importance of gene-gene and gene-environment interactions in the origins of these defects. A number of cell biological functions are essential for Neural Tube closure, with defects of the cytoskeleton, cell cycle and molecular regulation of cell viability prominent among the mouse NTD mutants. Many transcriptional regulators and proteins that affect chromatin structure are also required for Neural Tube closure, although the downstream molecular pathways regulated by these proteins is unknown. Some key signalling pathways for NTDs have been identified: over-activation of sonic hedgehog signalling and loss of function in the planar cell polarity (non-canonical Wnt) pathway are potent causes of NTD, with requirements also for retinoid and inositol signalling. Folic acid supplementation is an effective method for primary prevention of a proportion of NTDs in both humans and mice, although the embryonic mechanism of folate action remains unclear. Folic acid-resistant cases can be prevented by inositol supplementation in mice, raising the possibility that this could lead to an additional preventive strategy for human NTDs in future.
Scott F. Gilbert - One of the best experts on this subject based on the ideXlab platform.
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Formation of the Neural Tube
Developmental Biology, 2000Co-Authors: Scott F. GilbertAbstract:Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Formation of the Neural Tube. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10080/
James L Mills - One of the best experts on this subject based on the ideXlab platform.
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maternal vitamin b12 status and risk of Neural Tube defects in a population with high Neural Tube defect prevalence and no folic acid fortification
Pediatrics, 2009Co-Authors: Anne M Molloy, Peadar N Kirke, James Troendle, Helen Burke, Marie Sutton, Lawrence C Brody, John M Scott, James L MillsAbstract:OBJECTIVE. Folic acid fortification has reduced Neural Tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce Neural Tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by Neural Tube defect. Our objective was to quantify the effect of low B12 status on Neural Tube defect risk in a high-prevalence, unfortified population. METHODS. We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a Neural Tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous Neural Tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects. RESULTS. Mothers of children affected by Neural Tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by Neural Tube defect. Pregnancy blood B12 concentrations of CONCLUSIONS. Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for Neural Tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.
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homocysteine metabolism in pregnancies complicated by Neural Tube defects
The Lancet, 1995Co-Authors: James L Mills, Mary R Conley, P N Kirke, Joseph Mcpartlin, D G Weir, J M ScottAbstract:Abstract Folic acid taken around the time of conception can prevent many Neural-Tube defects. Women with low-normal vitamin B 12 values may also be at increased risk. We considered whether homocysteine metabolism via the enzyme methionine synthase, which requires both folate and B 12 , could be the critical defect in folate-related Neural Tube defects. Blood was obtained during pregnancies that produced 81 infants with Neural-Tube defects and 323 normal children. Samples were assayed for homocysteine, methylmalonic acid, plasma folate, red-cell folate, and B 12 . Mothers of children with Neural-Tube defects had significantly higher homocysteine values (8·62 [SD 2·8] μmol/L) than did B 12 -matched controls (7·96 [2·5] μmol/L, p=0·03). The difference was significant (p=0·004) in the lower half of the B 12 distribution after adjusting for plasma folate. Our study shows that an abnormality in homocysteine metabolism, apparently related to methionine synthase, is present in many women who give birth to children with Neural-Tube defects. Overcoming this abnormality is likely to be the mechanism by which folic acid prevents Neural-Tube defects. These findings suggest that the most effective periconceptional prophylaxis to prevent Neural-Tube defects may require B 12 as well as folic acid.
Richard H Finnell - One of the best experts on this subject based on the ideXlab platform.
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Pathobiology and genetics of Neural Tube defects.
Epilepsia, 2020Co-Authors: Richard H Finnell, Amy Gould, Ofer SpiegelsteinAbstract:Neural Tube defects (NTDs), including spina bifida and anencephaly, are common congenital malformations that occur when the Neural Tube fails to achieve proper closure during early embryogenesis. Based on epidemiological and clinical data obtained over the last few decades, it is apparent that these multifactorial defects have a significant genetic component to their etiology that interacts with specific environmental risk factors. The purpose of this review article is to synthesize the existing literature on the genetic factors contributing to NTD risk. To date, there is evidence that closure of the mammalian Neural Tube initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to an NTD, possibly arising through closure site-specific genetic mechanisms. Candidate genes involved in Neural Tube closure include genes of the folate metabolic pathway, as well as those involved in folate transport. Although extensive efforts have focused on elucidating the genetic risk factors contributing to the etiology of NTDs, the population burden for these malformations remains unknown. One group at high risk for having children with NTDs is epileptic women receiving antiepileptic medications during pregnancy. Efforts to better understand the genetic factors that may contribute to their heightened risk, as well as the pathogenesis of Neural Tube closure defects, are reviewed herein.
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Neural Tube defects and folate case far from closed
Nature Reviews Neuroscience, 2006Co-Authors: Henk J Blom, Gary M Shaw, Martin Den Heijer, Richard H FinnellAbstract:Failure of Neural Tube closure leads to Neural Tube defects, such as spina bifida and anencephaly, and has been linked to insufficiency of folate. The genetic and molecular mechanisms that link folate metabolism to Neural Tube defects are now being unravelled. Neural Tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of Neural Tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ∼50–75% of cases of Neural Tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents Neural Tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent Neural Tube defects.
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Pathobiology and genetics of Neural Tube defects
Epilepsia, 2003Co-Authors: Richard H Finnell, Amy Gould, Ofer SpiegelsteinAbstract:Summary: Purpose: Neural Tube defects (NTDs), including spina bifida and anencephaly, are common congenital malformations that occur when the Neural Tube fails to achieve proper closure during early embryogenesis. Based on epidemiological and clinical data obtained over the last few decades, it is apparent that these multifactorial defects have a significant genetic component to their etiology that interacts with specific environmental risk factors. The purpose of this review article is to synthesize the existing literature on the genetic factors contributing to NTD risk. Results: To date, there is evidence that closure of the mammalian Neural Tube initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to an NTD, possibly arising through closure site–specific genetic mechanisms. Candidate genes involved in Neural Tube closure include genes of the folate metabolic pathway, as well as those involved in folate transport. Conclusions: Although extensive efforts have focused on elucidating the genetic risk factors contributing to the etiology of NTDs, the population burden for these malformations remains unknown. One group at high risk for having children with NTDs is epileptic women receiving antiepileptic medications during pregnancy. Efforts to better understand the genetic factors that may contribute to their heightened risk, as well as the pathogenesis of Neural Tube closure defects, are reviewed herein.
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Genetics of Neural Tube defects.
Seminars in Pediatric Neurology, 2001Co-Authors: Janee Gelineau-van Waes, Richard H FinnellAbstract:Neural Tube defects (NTDs) are common congenital malformations that occur when the embryonic Neural Tube fails to close properly during early development. Although multifactorial in origin, NTDs appear to have a strong genetic component. Mouse NTD mutants provide useful models for the study of candidate genes involved in Neural Tube development and closure. Because maternal nutrition, specifically folate supplementation, is a significant modulator of NTD risk, genes involved in folate transport and metabolism are a focus of investigation. In addition, transcription factors, as well as genes involved in mitosis, actin regulation, and methylation, appear to be implicated in the causes of NTDs. The heterogeneity of function of candidate genes suggests that alterations in multiple developmental pathways may lead to the same clinical malformation.
