Human Molecular Genetics, 2000, Vol. 9, No. 6 993-1000
© 2000 Oxford University Press
Mouse models for neural tube closure defects
Department of Medical Genetics, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada V6T 1Z3
Received 4 February 2000; Accepted 14 February 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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Neural tube closure defects (NTDs), in particular anencephaly and spina bifida, are common human birth defects (1 in 1000), their genetics is complex and their risk is reduced by periconceptional maternal folic acid supplementation. There are >60 mouse mutants and strains with NTDs, many reported within the past 2 years. Not only are NTD mutations at loci widely heterogeneous in function, but also most of the mutants demonstrate variable low penetrance and some show complex inheritance patterns (e.g. SELH/Bc, Abl/Arg, Mena/Profilin1). In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones. NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid (Pax3, Cart1, Cd mutants), inositol (ct) and methionine (Axd). Lack of de novo methylation in embryos (Dnmt3b-null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants (Gadd45a, Terc, Trp53) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation (Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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Risk of a neural tube defect (NTD) is inherited in humans, but usually not as a single dominant or recessive gene. Risk varies with ethnic group, socioeconomic group and time, but approximates to 1 in 1000 births for anencephaly or spina bifida, and the risk of recurrence in a sibship is ~2–5% (1,2). In other words, human NTDs are common birth defects and the cause is genetically complex. Risk of both recurrence (3,4) and occurrence (5) has been observed to drop by up to 70% with the introduction of folic acid supplementation to the maternal diet before conception and during the first weeks of pregnancy, but the mechanism of prevention is not understood. Genetic variation in the components of folate metabolic pathways are being examined in humans for roles in NTDs, but it is not clear whether these variants are causative or are modifiers of NTD risk caused by certain alleles at other types of locus. In this review, we consider genetic NTDs in mice, in particular research reports in the past 2 years, and the insights that mouse NTD models contribute to understanding of human NTDs.
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A PLETHORA OF MUTANTS |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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A genetic model of common human NTDs seems likely to be a non-syndromic NTD with a degree of genetic complexity and/or low penetrance and/or response to nutritional supplementation. Few of the >60 mutations that cause NTDs in mice (Table 1) fit these criteria fully. Numerous gene-knockout (null) homozygotes have syndromes of multiple severe defects, lethal during embryogenesis, that include failure to close the neural tube, in particular in the head (Table 1). A similar phenotype in humans would register as early spontaneous abortion. However, there is a growing number of these genes, such as Apob (6) and Itgb1 (7), for which restoration of partial gene function leads to exencephaly in embryos that survive to late gestation.
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Mutations at many other loci cause NTDs that parallel the genetics of common human NTDs in having low and variable penetrance, an NTD that can be the only birth defect present, survival into at least the fetal period, and in some cases dietary modification of penetrance (Tables 1 and 2). Many of these NTD mutations cause other morphological defects, although not always in the same embryo that has an NTD, as in Macs (8) and Trp53 (9,10) mutants. Some of these are ‘classical’ mutations where the gene product is not known; several are targeted null or ectopic-expression mutations in known genes. They point to a heterogeneity of gene regulatory and metabolic pathways and to potential for extensive heterogeneity in human genetic risk factors for NTDs.
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Genetic complexity can be mechanistically different from the ‘major locus with modifiers’ situation that the gene-knockout approach seems to uncover. Transmission of risk can be caused by the cumulative effects of interchangeable loci or by interaction between specific alleles at two or more loci. Some genes with no morphological defects in null-mutation homozygotes have NTDs when combined with heterozygosity for a null mutation at another locus, as in Mena–/– with Profilin1+/– (11). There are also mouse strains that appear to have non-syndromic NTDs of multigenic complex genetic origin (Table 1), of which one, SELH/Bc (12,13), has been the focus of study. The complex genetics of NTD risk in such strains indicates that the genetics of at least some human NTDs may also be complex.
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MOST NTDS REFLECT FAILURE OF NEURAL FOLD ELEVATION IN MECHANISTICALLY DISTINCT ZONES |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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To create the neural tube, the embryonic neural folds undergo major morphological changes, elevating from a semi-horizontal to a vertical position, and shifting from convex to concave, so that their tips, formerly pointed away from the midline, tilt toward the midline, touch and fuse (Fig. 1B).
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The mouse neural tube consists of several cranio–caudal zones within which elevation passes as a wave longitudinally and, at discrete initial sites within each zone, the folds come into apposition, make first contact and fuse (14,15). From each initiation site (Closures 1, 2, 3 and 4), the contact and fusion extend, zipper-like, along the length of the folds until colliding with fusion initiated from another zone (Fig. 1A).
In nearly all the mouse NTD mutants examined, the exencephaly (the equivalent of human anencephaly), spina bifida (aperta) or rachischisis (Fig. 1A) arises from failure to complete the process of elevation of the neural folds to become vertical and concave (reviewed in ref. 16) and thus they do not make contact to fuse and form a tube. An additional NTD, encephalocele, where the defect occurs subsequent to neural fold elevation and fusion (2), is genetically distinct from other NTDs in mice (16), being present in only one mouse mutant (17), which has no other type of NTD.
Nearly all of the NTD mutations of mice cause specific types of NTD (reviewed in ref. 16), each reflecting the failure of elevation of the neural folds of particular elevation zones (Fig. 1). Most mutations cause only exencephaly (zone B or zones B + C). Several cause exencephaly and spina bifida (zone B and caudal zone D). Some cause a striking craniofacial defect of exencephaly with split face (zones B + A). A few cause only spina bifida (caudal zone D), and two cause rachischisis (whole of zone D).
The specificity of NTD types caused by each of the various NTD mutations in mice indicates that the spatially and chronologically distinct zones of neural fold elevation observed in normal embryos probably reflect a spatial and temporal heterogeneity of molecular mechanisms that engineer the transformation of neural fold morphology to produce the elevation necessary for closure.
The human NTDs, anencephaly, spina bifida and rachischisis, are anatomically similar to mouse NTDs, suggesting that they originate in failure of elevation of similar elevation zones (Fig. 1). Therefore, the NTD risk genes may well be homologues. Very few normal human embryos have been seen during this stage of development. The Closure 2 contact initiation site of mice may not be present in human embryos, where the ‘zipping’ process may extend rostrally from the Closure 1 initiation site to meet the ‘zipper’ from Closure 3 (18) (Fig. 1). However, if the defect in both species is a failure of elevation itself, a species difference in the location of first contact of already elevated folds would be subsequent to, and unrelated to, the cause of NTDs.
The independence of elevation zones and mechanisms is demonstrated clearly by the homozygous mutant looptail (19) and the early lethal Raldh2 gene knockout (20). All of zone D (Fig. 1) is unable to elevate, resulting in rachischisis, but zones A and B elevate and fuse normally. The looptail locus is not yet identified (21,22), but its abnormal function leads to an abnormally wide floorplate and notochord with abnormally broad expression domains of Sonic hedgehog, Netrin1 and Brachyury (19).
Genes that cause exencephaly alone point to a variety of mechanisms important to midbrain elevation (reviewed in ref. 16; references in Table 1); for example, normal neuroepithelial cell number (Apob), gap junctions (Gja1), basal laminae (Lama5), actin organization (Macs), transcription (p300 and Trp53) and DNA methyltransferase (Dnmt3b). Some transcription factors, such as Tcfap2a, seem to be essential to both the forebrain (Fig. 1, zone A) and midbrain (zone B) regions and adequate forebrain mesenchyme seems necessary for midbrain elevation (Cart1).
SELH/Bc mice, with a genetically multifactorial high risk of exencephaly (Table 1), offer other insights into the possible nature of risk of zone B NTDs in humans. All SELH/Bc embryos delay elevation of zone B and none make the normal initial contact at Closure 2. In ~20% the zone B (midbrain) folds never elevate, resulting in exencephaly. However, in the rest, the zone B folds do elevate in time for compensatory zipping from the Closure 3 initiation site to continue through zone B to meet the rostral end of zone C closure (14). Most of these embryos become normal adults, demonstrating that normal individuals can often emerge from ‘abnormal’ embryology. However, all SELH/Bc embryos pass through a developmental state perilously close to catastrophe (failure of zone B elevation) and are highly susceptible to exencephaly induced by maternal exposure to retinoic acid or valproic acid during this time (23,24).
Although caudal zone D and zone B elevation are not contemporaneous, most mouse mutations causing spina bifida also have risk of exencephaly (Table 1), a correlation that indicates that some of the same mechanisms are used in both zones. The mouse mutant loci include Mlp (with a role in actin organization), Nog (a signalling molecule), Pax3 (a transcription factor), open brain (opb) and curly tail (ct). Among these mutants, the developmental mechanism has been well studied in curly tail, where it has been shown that the spina bifida arises not from a defect in the neural tube itself, but from an abnormal curvature imposed on the neural tube by an abnormal delay in growth of the underlying ventral tailbud (which becomes the hindgut and notochord) (25,26).
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MATERNAL FOLIC ACID AND OTHER NUTRIENTS REDUCE RISK OF NTDS IN MOUSE MODELS |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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The compelling evidence that periconceptional supple- mentation of the maternal diet with folic acid reduces the risk of human NTD (anencephaly and spina bifida) by up to 70% has led to a search in both humans and mice for genetic defects in molecules involved in folate metabolism. The current story is incomplete but interesting. In humans, there is evidence from several populations that homozygosity in embryos for a common variant in the locus for the folate pathway enzyme, methylenetetrahydrofolate reductase (MTHFR), which leads to reduced enzyme activity, is associated with an increased risk of spina bifida (27–30). However, this variant can only partly explain the low folate status of NTD mothers (31). A common allele at the methionine synthase reductase (MTRR) locus has been reported to increase NTD risk when the vitamin B12 level is low or the MTHFR mutant genotype is present (32). No association between human NTDs and polymorphisms of methionine synthase (MTR) or cystathionine beta synthase (CBS) has been found (28,33–35). In mice, Cbs-null homo- zygotes are morphologically normal at birth (36). No data on null mutations of Mthfr, Mtrr, Mtr or dihydrofolate reductase (Dhfr) appear to have been published (37).
For the human folate-binding proteins, FR
and FRß [Folbp1 and Folbp2 in mice (38)], polymorphic markers showed no association with NTDs (35) and gene analysis found no gene defects in spina bifida cases (39). Mouse Folbp2-null homozygotes develop normally, but Folbp1-null homozygotes die by day 10 of gestation, with unclosed neural tubes (40). It will be interesting to see whether non-null mutations at Folbp1 cause risk of exencephaly or spina bifida.
Three mouse NTD mutants have shown a decreased risk of NTD in response to folic acid: crooked (Cd), splotch (Sp) and cartilage homeoprotein 1 (Cart1) (Table 2). Little is known about folate metabolism in Cart1 or crooked mutants. However, interestingly, homozygous splotch embryos (Pax3 mutants) have a metabolic deficiency in the supply of folate available for pyrimidine biosynthesis. The folate deficiency can be compensated for by maternal supplementation with folic acid or thymidine, either of which reduces the frequency of spina bifida in Sp/Sp embryos by 40% (41). Numerous early cellular defects are known in neural folds of splotch mutants (reviewed in ref. 16), but it is not yet known how the inherent folate deficiency connects with any of these potential mechanisms for failure of neural fold elevation. Pax3, a transcription factor, is not an obvious participant in a folate pathway; how its mutations cause a metabolic folate deficiency is not yet known.
In three mouse genetic NTDs tested, maternal folate supplementation has produced no decrease in NTD risk: axial defects (Axd), curly tail (ct) and SELH/Bc. But, for each model, a change in another component of maternal nutrition does cause a dramatic drop in NTD risk (Table 2). Each of these could be a good model with which to explore mechanisms of NTD prevention. In the curly tail model, inositol, apparently via protein kinase C, upregulates Rarb expression and growth at the site of the primary defect, a slow-growing hindgut (42). These mouse NTD models indicate that nutrients other than folic acid may be used to reduce NTD risk in non-folate-responsive human genotypes.
It has been suggested that the mechanism of prevention of human NTDs by maternal folate supplementation is by causing spontaneous abortion of ‘NTD’ embryos (43). In the mouse NTD mutants that respond to nutrients, there is no evidence of treatment-induced death of mutant embryos or NTD embryos.
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NTD RISK, GENDER BIAS IN NTDS AND GENOMIC INSTABILITY MAY SHARE A COMMON ROOT IN METHYLATION |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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There is an excess of females among human anencephalics (44) and in mouse exencephalics from a variety of genetic causes [curly tail, crooked, crn, Macs, Trp53, xn, NZW-xid and SELH/Bc (Table 1)]. Both sexes have exencephaly, but females have it more often. It is clear in at least some of the mouse mutants that this is due to a chromosomal gender effect on neural fold elevation itself (not death of NTD males). During neural fold elevation, the gonads have not yet formed, and the mechanism of the gender effect has been mystifying. In such biological oddities often lie clues to mechanisms, and this may be the case for NTDs. The known difference between males and females during neural fold elevation is the presence, in all female cells, of an inactivated, highly methylated, second X chromosome. After each cell division in female embryos, the second, relatively large, X chromosome in every new cell must be methylated. It seems reasonable to suppose that a difference between males and females in rapidly growing, elevating, cranial neural fold cells could be a lesser availability of methylation for other needs in female cells (methylation of DNA, protein, lipids), including one with a key role in a mechanism essential to neural fold elevation. In this context, it is intriguing that Dnmt3b, responsible for de novo methylation of DNA in mouse embryos, is specifically strongly expressed in elevating cranial neural folds, and its null mutation leads to exencephaly (45).
Methionine (a source of methyl groups) is essential to neural fold elevation in whole embryo culture (46). The methylation cycle is a part of folate metabolic pathways, connected through methionine synthase.
One of the important functions of methylation of DNA in early embryos is thought to be the suppression of the transcription (47), replication and transposition (48) of the numerous transposable elements (TEs) embedded in the genome. New transposition of TEs into genes causes mutations. In the SELH/Bc strain, high risk of exencephaly with female excess (14) is accompanied by a high rate of new heritable non-NTD mutations, apparently due to failure to suppress transposition of ‘early transposon’ (ETn) elements in early embryos (49), leading to a hypothesis that SELH/Bc embryos have inadequate DNA methylation capacity.
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ACTIN-RELATED NTD MUTANTS INDICATE A KEY ROLE OF ACTIN IN NEURAL FOLD ELEVATION |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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The genes involved in a growing list of mouse NTD mutants have some role in the organization of actin molecules in the cytoskeleton. A long-standing hypothesis suggests that part of the force required to change the shape of the neural folds from flat or convex to concave, to elevate, is a ‘purse-string’ rearrangement of actin at the lumenal/apical surface, changing the neuroepithelial cells from columnar to wedge-shaped (50). NTD mutations in two related genes that regulate actin arrangement at the cell membrane [Macs (8,51) and Mlp (52,53)] have been known for several years, and four more actin-related NTD mutants have been reported recently: Abl/Arg (54), vinculin [Vcl (55)], Mena/Profilin1 (11) and Shrm (56). In all cases, cranial (zone B) neural fold elevation fails, causing exencephaly. The expression domains of all of these genes except Vcl have been examined and have been shown to include the cranial neural folds during elevation. In addition to exencephaly, both Mlp and Shrm have spina bifida (caudal zone D failure) and both Shrm and Vcl have split face (zone A failure). The penetrance was incomplete for all mutations except Shrm and Vcl. Taken together, this functional clustering of NTD mutations in genes involved in actin binding and rearrangement and expressed in the neuroepithelium of the elevating neural folds, indicates that a mechanism leading to these NTDs may well be in the lack of morphogenetic force normally provided by the apical redistribution of actin.
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NEW NTD MUTANTS POINT TO A RELATIONSHIP BETWEEN NTDS AND STRUCTURAL INSTABILITY OF CHROMOSOMES |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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Terc-null homozygotes have a risk of exencephaly, spina bifida and split face (57). Terc, the RNA component of telomerase, functions as the template for adding new telomeric repeats to the ends of chromosomes, to maintain their length through cell divisions; telomere shortening leads to cell senescence. Terc is transcribed at high levels in the neural folds before and during neural fold elevation (in particular zones A and B). In Terc-null homozygotes, telomeres shortened and NTD frequency rose with each generation to 30% by the fifth generation, when Terc-null lineages die out. Why the neural fold cells transcribe particularly high levels of Terc and why they need it for neural fold elevation is an intriguing question.
Gadd45a-null homozygotes have an ~10% risk of exencephaly, and are otherwise viable and fertile (58). Gadd45a is a nuclear protein with a role in regulating the cell cycle and stabilizing chromosomes in mitosis. Gadd45a expression is regulated by p53 (Trp53). Trp53-null homo- zygotes also have a 10% risk of exencephaly, the other 90% being viable and fertile (9,10). Both Gadd45a-null and Trp53-null cells acquire multiple chromosomal anomalies. The nature of the connection between the chromosomal mitotic instability and failure of cranial neural fold elevation in Gadd45a-null and Trp53-null embryos is another intriguing question.
Taken together, the Terc, Gadd45a and Trp53 NTD mutants suggest that mechanisms of neural fold elevation may commandeer cellular machinery that is otherwise part of basic mitosis.
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HUMAN HOMOLOGUES OF MOUSE NTD GENES? |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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Numerous unpublished NTD mutations are in the pipeline, e.g. exma (59). Few of the loci implicated in NTD defects in mice have been screened for mutations in human NTD cases. Screens of human NTD cases for association with PAX3 (35,60) and BRCA1 (33) variants found no evidence for their involvement in common human NTD. A report of mild association between human NTD and the region of the T locus homologue (33) has not been supported by another study (35). For most mouse NTDs, there is still a ‘black box’ between knowing a gene involved in NTDs and knowing the morphogenetic mechanism it contributes to neural fold elevation. Some excellent candidates from mouse NTD models to be investigated in human NTDs are emerging, such as the actin-related genes. The specific occurrence of NTDs in other new mouse mutants, such as those involved in maintenance of chromosome length and stability in mitosis, suggests that there are surprises waiting on the road to understanding NTDs.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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D.M.J. and M.J.H. are supported by grants from the Medical Research Council of Canada.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 604 822 5786; Fax: +1 604 822 5348; Email: juriloff@interchange.ubc.ca
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REFERENCES |
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TOPABSTRACTINTRODUCTIONA PLETHORA OF MUTANTSMOST NTDS REFLECT FAILURE...MATERNAL FOLIC ACID AND...NTD RISK, GENDER BIAS...ACTIN-RELATED NTD MUTANTS...NEW NTD MUTANTS POINT...HUMAN HOMOLOGUES OF MOUSE...ACKNOWLEDGMENTSREFERENCES |
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C. H. Regnier, R. Masson, V. Kedinger, J. Textoris, I. Stoll, M.-P. Chenard, A. Dierich, C. Tomasetto, and M.-C. Rio Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice PNAS, April 16, 2002; 99(8): 5585 - 5590. [Abstract] [Full Text] [PDF]
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B Richter, A H Schultealbert, and M C Koch Human T and risk for neural tube defects J. Med. Genet., March 1, 2002; 39(3): e14 - 14. [Full Text] [PDF]
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J. P. M. Barbera, T. A. Rodriguez, N. D. E. Greene, W. J. Weninger, A. Simeone, A. J. Copp, R. S. P. Beddington, and S. Dunwoodie Folic acid prevents exencephaly in Cited2 deficient mice Hum. Mol. Genet., February 1, 2002; 11(3): 283 - 293. [Abstract] [Full Text] [PDF]
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J. K. Kim, S.-O. Huh, H. Choi, K.-S. Lee, D. Shin, C. Lee, J.-S. Nam, H. Kim, H. Chung, H. W. Lee, et al. Srg3, a Mouse Homolog of Yeast SWI3, Is Essential for Early Embryogenesis and Involved in Brain Development Mol. Cell. Biol., November 15, 2001; 21(22): 7787 - 7795. [Abstract] [Full Text] [PDF]
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J. N. Murdoch, K. Doudney, C. Paternotte, A. J. Copp, and P. Stanier Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification Hum. Mol. Genet., October 1, 2001; 10(22): 2593 - 2601. [Abstract] [Full Text] [PDF]
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N. Honarpour, S. L. Gilbert, B. T. Lahn, X. Wang, and J. Herz Apaf-1 deficiency and neural tube closure defects are found in fog mice PNAS, August 14, 2001; 98(17): 9683 - 9687. [Abstract] [Full Text] [PDF]
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A. Ikeda, S. Ikeda, T. Gridley, P. M. Nishina, and J. K. Naggert Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice Hum. Mol. Genet., June 1, 2001; 10(12): 1325 - 1334. [Abstract] [Full Text] [PDF]
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C. H. Regnier, R. Masson, V. Kedinger, J. Textoris, I. Stoll, M.-P. Chenard, A. Dierich, C. Tomasetto, and M.-C. Rio Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice PNAS, April 16, 2002; 99(8): 5585 - 5590. [Abstract] [Full Text] [PDF]
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