The Experts below are selected from a list of 2022 Experts worldwide ranked by ideXlab platform
D M Juriloff - One of the best experts on this subject based on the ideXlab platform.
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mouse mutants with neural tube closure defects and their role in understanding human neural tube defects
Birth Defects Research Part A-clinical and Molecular Teratology, 2007Co-Authors: M J Harris, D M JuriloffAbstract:BACKGROUND: The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight "multifactorial" strains. METHODS: The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta. RESULTS: Of the 150 mouse mutants that survive past midgestation, 20% have risk of either Exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only Exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the "multifactorial" strains and several null-mutant heterozygotes and mutants with partial gene function (hypomorphs) have low-penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse Exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains. CONCLUSIONS: If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low-penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain.
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maternal diet alters Exencephaly frequency in selh bc strain mouse embryos
Birth Defects Research Part A-clinical and Molecular Teratology, 2005Co-Authors: M J Harris, D M JuriloffAbstract:BACKGROUND The SELH/Bc mouse inbred strain, with a high frequency of nonsyndromic, genetically-multifactorial Exencephaly, is a model for human cranial neural tube defects (NTDs). Maternal diet affects risk of human NTDs. METHODS Exencephaly frequencies in SELH/Bc embryos were compared in 8 studies in which dams were fed alternative commercial Purina diets (5015 and 5001) or semisynthetic diets, and in several studies in which maternal diet was supplemented with a specific nutrient, either in drinking water or food before and during pregnancy, or by intraperitoneal injection on E7 and/or E8. RESULTS The Exencephaly frequency in SELH/Bc embryos was 2- to 8-fold higher when the dams were fed Purina 5015 (averaging 23% Exencephaly) or a semisynthetic diet modeled on Purina 5015 (averaging 28%) or NIH-31 standard diet (23%), compared with Purina 5001 (averaging 7%). The Exencephaly frequency remained high (41%) on a semisynthetic diet modeled on Purina 5001. The Exencephaly frequency was not reduced significantly by maternal supplementation with folic acid, nor with each of zinc, methionine, niacin, brewers' yeast, riboflavin, vitamin B12, or inositol. Nor was it reduced by maternal diets with supplemental methyl donors and cofactors or with reduced fat. CONCLUSIONS The frequency of Exencephaly in SELH/Bc embryos is strongly influenced by a specific unidentified aspect of the commercial ration Purina 5001 that prevents 55–85% of Exencephaly in SELH/Bc embryos, when directly compared with an alternative commercial ration Purina 5015 or its semisynthetic mimic. This strong maternal diet effect on NTD frequency may point to novel nutritional approaches to prevention of human NTDs. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc.
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multifactorial genetics of Exencephaly in selh bc mice
Teratology, 2001Co-Authors: D M Juriloff, T M Gunn, M J Harris, D G Mah, Sarah L DewellAbstract:Background The SELH/Bc mouse strain has 10–30% Exencephaly and is an animal model for human neural tube closure defects. This study examined the number of causative genes, their dominance relationships, and linkage map positions. Methods The SELH/Bc strain (S) was crossed to the normal LM/Bc strain (L) and frequencies of Exencephaly were observed in the F1, BC1, and F2 generations. 102 F2 males were individually testcrossed by SELH/Bc. The extremes, the 10 highest and 10 zero Exencephaly-producing F2 sires, were typed for 109 SSLP marker loci in a genome screen. Next, the resultant five provisional chromosomal regions were tested for linkage in 31 F2 exencephalic embryos. Finally, 12 males, SS or LL for the Chr 13 region on an LM/Bc background, were testcrossed by SELH/Bc. Results The Exencephaly frequencies in the F1 (0.3%), BC1 (4.4%), and F2 (3.7%), and the distribution of F2 males' testcross values (0–15.5%), indicated that the high risk of Exencephaly in SELH/Bc is due to the cumulative effect of two or three loci. Linkage studies indicated the location of semidominant Exencephaly-risk genes on Chr 13 near D13Mit13 (P < 0.001), Chr 5 near D5Mit168 (P < 0.025), and possibly Chr 11 near D11Mit10 (P < 0.07). The gene on Chr 13, Exen1, and the strong role of other loci were confirmed by the congenic males. Conclusions The high risk of Exencephaly in SELH/Bc mice is caused by the cumulative effect of two to three semidominant genes. Candidate genes include Msx2, Madh5, Ptch, and Irx1 (Chr 13) and Actb and Rac1 (Chr 5). Teratology 64:189–200, 2001. © 2001 Wiley-Liss, Inc.
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effect of multifactorial genetic liability to Exencephaly on the teratogenic effect of valproic acid in mice
Teratology, 1997Co-Authors: J L Hall, M J Harris, D M JuriloffAbstract:The present study shows that the multifactorial genetic liability to spontaneous Exencephaly in the SELH/Bc mouse strain (10-20% of embryos) also confers an elevated risk of Exencephaly induced by valproic acid. Treatment of pregnant dams (600 mg/kg sodium valproate in distilled water, i.p.) during the critical period on day 8 (D8) of gestation resulted in D14 Exencephaly frequencies of 69% in SELH/Bc contrasted with 39% in each of the SWV/Bc and ICR/Bc strains. Analysis of these data under the assumptions of the threshold model indicated that the valproic acid-induced-shift in mean liability was similar for all three strains, and therefore the effects of genotype and teratogen were additive, not synergistic. A similar Exencephaly response pattern for the same three strains was observed previously with retinoic acid [Tom et al. (1991) Teratology 43:27-40], a pattern that, combined with the data of Finnell et al. [(1988) Teratology 38:313-320], argues that strain differences in Exencephaly response are not due to strain differences in teratogen metabolism. SWV/Bc and ICR/Bc embryos differ in location of the Closure 2 initiation site of cranial neural tube closure [Juriloff et al. (1991) Teratology 44:225-233], but the observation that they do not differ in risk of Exencephaly produced by either valproic acid or retinoic acid contradicts the hypothesis that this particular morphological difference underlies strain differences in Exencephaly risk. The high Exencephaly response of SELH/Bc to two teratogens predicts that human conceptuses with a genetically determined elevated risk for neural tube defects could be easily tipped into high risk by mild teratogens.
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Exencephaly and cleft cerebellum in selh bc mouse embryos are alternative developmental consequences of the same underlying genetic defect
Teratology, 1996Co-Authors: T M Gunn, D M Juriloff, M J HarrisAbstract:SELH/Bc inbred mice have ataxia in 5–10% of young adults and Exencephaly in 10–20% of newborns. SELH/Bc mice also have a high rate of spontaneous mutation and therefore it could not be assumed that these two abnormalities share the same genetic cause. Previously, we have shown that the liability to Exencephaly in SELH/Bc mice is multifactorial, involving two to three loci, and that all the ataxics have a midline cleft cerebellum. The purpose of the present study was to resolve the genetic relationship between liability to Exencephaly and liability to cleft cerebellum. We tested whether these traits were transmitted together by segregating F2 males; cotransmission would indicate that both traits are probably caused by the same genes. Approximately 100 embryos from each of 25 F2 sires from a cross between SELH/Bc and the normal LM/Bc strain were scored for Exencephaly and the non-exencephalic embryos were scored for cleft cerebellum. The range of Exencephaly production by these 25 F2 sires was 0% to 16%; the sires had been selected to represent the extremes of the range of Exencephaly production. We found that the 10 sires that produced no Exencephaly also produced no cleft cerebellum and 12 of the 15 sires that produced some Exencephaly also produced some cleft cerebellum. This indicated strongly that the two traits are transmitted together (Fisher's exact test, P < 0.0002). Furthermore, within Exencephaly-producing sires, the specific frequencies of the two traits were significantly positively correlated (Spearman rs = 0.58; P < 0.05), indicating that the same multifactorial risk factors influence both traits. All SELH/Bc embryos omit one normal initiation site of cranial neural tube closure, Closure 2. In a previous study, absence of the Closure 2 initiation site of cranial neural tube closure has been shown to be genetically correlated with liability to Exencephaly. In the second part of the present study, the same Closure 2 data from eight of the F2 sires were observed to be significantly positively correlated with liability to cleft cerebellum (Spearman rs = 0.83; P < 0.05). The results of this genetic approach have supported the hypothesis, based on observation of embryos, that one basic multifactorial genetic defect in SELH mice leads to an abnormal cranial neural tube closure mechanism, to Exencephaly, to cleft cerebellum, and to ataxia. Teratology 54: 230–236 © 1997 Wiley-Liss, Inc.
M J Harris - One of the best experts on this subject based on the ideXlab platform.
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mouse mutants with neural tube closure defects and their role in understanding human neural tube defects
Birth Defects Research Part A-clinical and Molecular Teratology, 2007Co-Authors: M J Harris, D M JuriloffAbstract:BACKGROUND: The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight "multifactorial" strains. METHODS: The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta. RESULTS: Of the 150 mouse mutants that survive past midgestation, 20% have risk of either Exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only Exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the "multifactorial" strains and several null-mutant heterozygotes and mutants with partial gene function (hypomorphs) have low-penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse Exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains. CONCLUSIONS: If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low-penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain.
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maternal diet alters Exencephaly frequency in selh bc strain mouse embryos
Birth Defects Research Part A-clinical and Molecular Teratology, 2005Co-Authors: M J Harris, D M JuriloffAbstract:BACKGROUND The SELH/Bc mouse inbred strain, with a high frequency of nonsyndromic, genetically-multifactorial Exencephaly, is a model for human cranial neural tube defects (NTDs). Maternal diet affects risk of human NTDs. METHODS Exencephaly frequencies in SELH/Bc embryos were compared in 8 studies in which dams were fed alternative commercial Purina diets (5015 and 5001) or semisynthetic diets, and in several studies in which maternal diet was supplemented with a specific nutrient, either in drinking water or food before and during pregnancy, or by intraperitoneal injection on E7 and/or E8. RESULTS The Exencephaly frequency in SELH/Bc embryos was 2- to 8-fold higher when the dams were fed Purina 5015 (averaging 23% Exencephaly) or a semisynthetic diet modeled on Purina 5015 (averaging 28%) or NIH-31 standard diet (23%), compared with Purina 5001 (averaging 7%). The Exencephaly frequency remained high (41%) on a semisynthetic diet modeled on Purina 5001. The Exencephaly frequency was not reduced significantly by maternal supplementation with folic acid, nor with each of zinc, methionine, niacin, brewers' yeast, riboflavin, vitamin B12, or inositol. Nor was it reduced by maternal diets with supplemental methyl donors and cofactors or with reduced fat. CONCLUSIONS The frequency of Exencephaly in SELH/Bc embryos is strongly influenced by a specific unidentified aspect of the commercial ration Purina 5001 that prevents 55–85% of Exencephaly in SELH/Bc embryos, when directly compared with an alternative commercial ration Purina 5015 or its semisynthetic mimic. This strong maternal diet effect on NTD frequency may point to novel nutritional approaches to prevention of human NTDs. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc.
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multifactorial genetics of Exencephaly in selh bc mice
Teratology, 2001Co-Authors: D M Juriloff, T M Gunn, M J Harris, D G Mah, Sarah L DewellAbstract:Background The SELH/Bc mouse strain has 10–30% Exencephaly and is an animal model for human neural tube closure defects. This study examined the number of causative genes, their dominance relationships, and linkage map positions. Methods The SELH/Bc strain (S) was crossed to the normal LM/Bc strain (L) and frequencies of Exencephaly were observed in the F1, BC1, and F2 generations. 102 F2 males were individually testcrossed by SELH/Bc. The extremes, the 10 highest and 10 zero Exencephaly-producing F2 sires, were typed for 109 SSLP marker loci in a genome screen. Next, the resultant five provisional chromosomal regions were tested for linkage in 31 F2 exencephalic embryos. Finally, 12 males, SS or LL for the Chr 13 region on an LM/Bc background, were testcrossed by SELH/Bc. Results The Exencephaly frequencies in the F1 (0.3%), BC1 (4.4%), and F2 (3.7%), and the distribution of F2 males' testcross values (0–15.5%), indicated that the high risk of Exencephaly in SELH/Bc is due to the cumulative effect of two or three loci. Linkage studies indicated the location of semidominant Exencephaly-risk genes on Chr 13 near D13Mit13 (P < 0.001), Chr 5 near D5Mit168 (P < 0.025), and possibly Chr 11 near D11Mit10 (P < 0.07). The gene on Chr 13, Exen1, and the strong role of other loci were confirmed by the congenic males. Conclusions The high risk of Exencephaly in SELH/Bc mice is caused by the cumulative effect of two to three semidominant genes. Candidate genes include Msx2, Madh5, Ptch, and Irx1 (Chr 13) and Actb and Rac1 (Chr 5). Teratology 64:189–200, 2001. © 2001 Wiley-Liss, Inc.
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effect of multifactorial genetic liability to Exencephaly on the teratogenic effect of valproic acid in mice
Teratology, 1997Co-Authors: J L Hall, M J Harris, D M JuriloffAbstract:The present study shows that the multifactorial genetic liability to spontaneous Exencephaly in the SELH/Bc mouse strain (10-20% of embryos) also confers an elevated risk of Exencephaly induced by valproic acid. Treatment of pregnant dams (600 mg/kg sodium valproate in distilled water, i.p.) during the critical period on day 8 (D8) of gestation resulted in D14 Exencephaly frequencies of 69% in SELH/Bc contrasted with 39% in each of the SWV/Bc and ICR/Bc strains. Analysis of these data under the assumptions of the threshold model indicated that the valproic acid-induced-shift in mean liability was similar for all three strains, and therefore the effects of genotype and teratogen were additive, not synergistic. A similar Exencephaly response pattern for the same three strains was observed previously with retinoic acid [Tom et al. (1991) Teratology 43:27-40], a pattern that, combined with the data of Finnell et al. [(1988) Teratology 38:313-320], argues that strain differences in Exencephaly response are not due to strain differences in teratogen metabolism. SWV/Bc and ICR/Bc embryos differ in location of the Closure 2 initiation site of cranial neural tube closure [Juriloff et al. (1991) Teratology 44:225-233], but the observation that they do not differ in risk of Exencephaly produced by either valproic acid or retinoic acid contradicts the hypothesis that this particular morphological difference underlies strain differences in Exencephaly risk. The high Exencephaly response of SELH/Bc to two teratogens predicts that human conceptuses with a genetically determined elevated risk for neural tube defects could be easily tipped into high risk by mild teratogens.
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Exencephaly and cleft cerebellum in selh bc mouse embryos are alternative developmental consequences of the same underlying genetic defect
Teratology, 1996Co-Authors: T M Gunn, D M Juriloff, M J HarrisAbstract:SELH/Bc inbred mice have ataxia in 5–10% of young adults and Exencephaly in 10–20% of newborns. SELH/Bc mice also have a high rate of spontaneous mutation and therefore it could not be assumed that these two abnormalities share the same genetic cause. Previously, we have shown that the liability to Exencephaly in SELH/Bc mice is multifactorial, involving two to three loci, and that all the ataxics have a midline cleft cerebellum. The purpose of the present study was to resolve the genetic relationship between liability to Exencephaly and liability to cleft cerebellum. We tested whether these traits were transmitted together by segregating F2 males; cotransmission would indicate that both traits are probably caused by the same genes. Approximately 100 embryos from each of 25 F2 sires from a cross between SELH/Bc and the normal LM/Bc strain were scored for Exencephaly and the non-exencephalic embryos were scored for cleft cerebellum. The range of Exencephaly production by these 25 F2 sires was 0% to 16%; the sires had been selected to represent the extremes of the range of Exencephaly production. We found that the 10 sires that produced no Exencephaly also produced no cleft cerebellum and 12 of the 15 sires that produced some Exencephaly also produced some cleft cerebellum. This indicated strongly that the two traits are transmitted together (Fisher's exact test, P < 0.0002). Furthermore, within Exencephaly-producing sires, the specific frequencies of the two traits were significantly positively correlated (Spearman rs = 0.58; P < 0.05), indicating that the same multifactorial risk factors influence both traits. All SELH/Bc embryos omit one normal initiation site of cranial neural tube closure, Closure 2. In a previous study, absence of the Closure 2 initiation site of cranial neural tube closure has been shown to be genetically correlated with liability to Exencephaly. In the second part of the present study, the same Closure 2 data from eight of the F2 sires were observed to be significantly positively correlated with liability to cleft cerebellum (Spearman rs = 0.83; P < 0.05). The results of this genetic approach have supported the hypothesis, based on observation of embryos, that one basic multifactorial genetic defect in SELH mice leads to an abnormal cranial neural tube closure mechanism, to Exencephaly, to cleft cerebellum, and to ataxia. Teratology 54: 230–236 © 1997 Wiley-Liss, Inc.
T M Gunn - One of the best experts on this subject based on the ideXlab platform.
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multifactorial genetics of Exencephaly in selh bc mice
Teratology, 2001Co-Authors: D M Juriloff, T M Gunn, M J Harris, D G Mah, Sarah L DewellAbstract:Background The SELH/Bc mouse strain has 10–30% Exencephaly and is an animal model for human neural tube closure defects. This study examined the number of causative genes, their dominance relationships, and linkage map positions. Methods The SELH/Bc strain (S) was crossed to the normal LM/Bc strain (L) and frequencies of Exencephaly were observed in the F1, BC1, and F2 generations. 102 F2 males were individually testcrossed by SELH/Bc. The extremes, the 10 highest and 10 zero Exencephaly-producing F2 sires, were typed for 109 SSLP marker loci in a genome screen. Next, the resultant five provisional chromosomal regions were tested for linkage in 31 F2 exencephalic embryos. Finally, 12 males, SS or LL for the Chr 13 region on an LM/Bc background, were testcrossed by SELH/Bc. Results The Exencephaly frequencies in the F1 (0.3%), BC1 (4.4%), and F2 (3.7%), and the distribution of F2 males' testcross values (0–15.5%), indicated that the high risk of Exencephaly in SELH/Bc is due to the cumulative effect of two or three loci. Linkage studies indicated the location of semidominant Exencephaly-risk genes on Chr 13 near D13Mit13 (P < 0.001), Chr 5 near D5Mit168 (P < 0.025), and possibly Chr 11 near D11Mit10 (P < 0.07). The gene on Chr 13, Exen1, and the strong role of other loci were confirmed by the congenic males. Conclusions The high risk of Exencephaly in SELH/Bc mice is caused by the cumulative effect of two to three semidominant genes. Candidate genes include Msx2, Madh5, Ptch, and Irx1 (Chr 13) and Actb and Rac1 (Chr 5). Teratology 64:189–200, 2001. © 2001 Wiley-Liss, Inc.
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Exencephaly and cleft cerebellum in selh bc mouse embryos are alternative developmental consequences of the same underlying genetic defect
Teratology, 1996Co-Authors: T M Gunn, D M Juriloff, M J HarrisAbstract:SELH/Bc inbred mice have ataxia in 5–10% of young adults and Exencephaly in 10–20% of newborns. SELH/Bc mice also have a high rate of spontaneous mutation and therefore it could not be assumed that these two abnormalities share the same genetic cause. Previously, we have shown that the liability to Exencephaly in SELH/Bc mice is multifactorial, involving two to three loci, and that all the ataxics have a midline cleft cerebellum. The purpose of the present study was to resolve the genetic relationship between liability to Exencephaly and liability to cleft cerebellum. We tested whether these traits were transmitted together by segregating F2 males; cotransmission would indicate that both traits are probably caused by the same genes. Approximately 100 embryos from each of 25 F2 sires from a cross between SELH/Bc and the normal LM/Bc strain were scored for Exencephaly and the non-exencephalic embryos were scored for cleft cerebellum. The range of Exencephaly production by these 25 F2 sires was 0% to 16%; the sires had been selected to represent the extremes of the range of Exencephaly production. We found that the 10 sires that produced no Exencephaly also produced no cleft cerebellum and 12 of the 15 sires that produced some Exencephaly also produced some cleft cerebellum. This indicated strongly that the two traits are transmitted together (Fisher's exact test, P < 0.0002). Furthermore, within Exencephaly-producing sires, the specific frequencies of the two traits were significantly positively correlated (Spearman rs = 0.58; P < 0.05), indicating that the same multifactorial risk factors influence both traits. All SELH/Bc embryos omit one normal initiation site of cranial neural tube closure, Closure 2. In a previous study, absence of the Closure 2 initiation site of cranial neural tube closure has been shown to be genetically correlated with liability to Exencephaly. In the second part of the present study, the same Closure 2 data from eight of the F2 sires were observed to be significantly positively correlated with liability to cleft cerebellum (Spearman rs = 0.83; P < 0.05). The results of this genetic approach have supported the hypothesis, based on observation of embryos, that one basic multifactorial genetic defect in SELH mice leads to an abnormal cranial neural tube closure mechanism, to Exencephaly, to cleft cerebellum, and to ataxia. Teratology 54: 230–236 © 1997 Wiley-Liss, Inc.
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genetically determined absence of an initiation site of cranial neural tube closure is causally related to Exencephaly in selh bc mouse embryos
Teratology, 1995Co-Authors: T M Gunn, D M Juriloff, M J HarrisAbstract:The SELH/Bc mouse strain (SELH) has a high frequency of the lethal neural tube closure defect, Exencephaly, in newborns and embryos. Previous work has shown that all SELH mouse embryos have an abnormal mechanism of rostral neural tube closure. They lack initiation of contact and fusion of the cranial neural tube at the prosencephalon/mesencephalon boundary [Closure 2), and undergo closure by extension of a more rostral site of fusion. This process fails in 10-20% of embryos, where the mesencephalic folds remain unelevated, resulting in Exencephaly. Previous work has also shown that the cause of liability to Exencephaly in SELH mice is multigenic, involving a small number of loci. The purpose of the present study was to test the hypothesis that the genes causing the lack of Closure 2 also cause the liability to Exencephaly in SELH, by observation of their joint transmission from genetically segregating animals. A concurrent mapping study provided the necessary genetic material, a segregating F2 generation from a cross of SELH with the normal LM/Bc strain. The genetic liability to Exencephaly transmitted by individual F2 sires had been measured by the frequencies of exencephalic day 14 embryos they produced in test-crosses with SELH females. A selected subset of 13 of these test-crossed F2 sires was bred with a second set of SELH females, and the embryos were examined earlier, during the period of neural tube closure, on days 8 and 9 of gestation, to determine the presence of Closure 2. Six F2 sires were among the highest Exencephaly producers (6-11%), six were among the lowest (0%), and one was intermediate (5%). Among embryos at the appropriate stage for scoring, the presence of Closure 2 was observed to be inversely correlated with the later risk of Exencephaly, being present in 93% (71/76) from the low-risk sires and 35% (36/103) from the high-risk sires. In each case, the remaining embryos had a closure mechanism like that of SELH embryos. Among the individual intermediate- and high-risk sires, there was also a clear correlation between the frequency of Exencephaly in older embryos and the frequency of lack of Closure 2 in early embryos (rs = 0.88; P < 0.05). This study demonstrates that high liability to Exencephaly and absence of Closure 2 are genetically transmitted together. That is, the cause of the lack of Closure 2 in SELH mice is shown to be also the probable cause of the high liability to Exencephaly.
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mapping genes for liability to Exencephaly in selh bc mice
American Journal of Human Genetics, 1994Co-Authors: T M Gunn, D M JuriloffAbstract:Exencephaly occurs in 6-20% of SELH/Bc strain mouse embryos. Liability to the cranial neural tube closure defect in SELH/Bc is multigenic, making it a good animal model for the study of the common human homolog, anencephaly. Our previous studies showed that the Exencephaly-liability in SELH/Bc is caused by 2 or 3 loci. We have undertaken to map these genes. We crossed SELH/Bc to the normal strain, LM/Bc, and are using the F{sub 2}generation to map the segregating liability loci. 100 F{sub 2} males are being testcrossed to SELH/Bc to determine their genetic liability to Exencephaly (based on frequency produced in their offspring, 100 scoreable embryos each). 83 males have been tested to date, producing Exencephaly frequencies of between 0% and 16%. 26 have produced 0% Exencephaly; 10 have produced at least 6%. These frequencies indicate that fewer than four Exencephaly-liability loci are segregating. DNA from the 10 F{sub 2} males that produce the highest frequency of Exencephaly and 10 that produce no Exencephaly are being typed for microsatellite markers covering the 19 autosomes at 20 cM (or less) intervals. Of the 221 markers typed to date, 94 (43%) are detectably different between SELH/Bc and LM/Bc. Preliminary data based on fivemore » 0% males and five {open_quotes}high{close_quotes} males has excluded several chromosomal regions for the presence of an Exencephaly-liability locus; e.g., most of chromosomes 2, 3, 4, 7, 12, 15, 17, and 19. The preliminary data suggest that there may be an Exencephaly-liability locus on chromosome 13.« less
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ataxia and a cerebellar defect in the Exencephaly prone selh bc mouse stock
Teratology, 1993Co-Authors: D M Juriloff, T M Gunn, M J Harris, M L Harrod, J E MillerAbstract:SELH/Bc inbred mice have an abnormal mechanism of anterior neural tube closure and 10–20% of embryos have a lethal neural tube closure defect, Exencephaly. Our previous studies have focused on this multifactorial threshold trait. However, SELH mice are also characterized by another trait that also shows non-Mendelian transmission ratios, an ataxia recognized in juvenile and adult mice. Here we report our first genetic and morphological studies of the ataxia trait. Recent pedigree records for the SELH colony showed that 7% of the 467 weaned progeny from normal breeding pairs were ataxic; 17 of the 20 pairs produced ataxic progeny. This result was statistically consistent with the hypothesis that all SELH mice have the ataxic genotype, which is expressed in only 7% of them. Genetic studies of an outcross to a normal strain and the subsequent F2 and testcross of the F2 were also done. The results were consistent with a one or two gene locus cause of liability to ataxia in SELH mice. The genetic correlation between Exencephaly production and ataxia production for a sample of nine F2 males was 0.35, as expected if both traits are caused by the same genes, but was not statistically significant. In another approach, we examined the morphology of brains from normal and ataxic adult SELH mice. All 20 brains from non-ataxic SELH mice were morphologically normal. In all 18 brains from ataxic SELH mice the cerebellum was abnormal, lacking the vermis, and characterized by a midline fissure. This phenotype in mice has previously been known in Mendelian mutants at the Wnt-1 locus. Our observations in SELH mice suggest that these cerebellar defects can also show multifactorial threshold patterns of occurrence. Because the site of origin of the cerebellum is the site of maximal delay in neural tube closure in SELH mice, the Exencephaly and ataxia may share a common genetic etiology. © 1993 Wiley-Liss, Inc.
L Cabero - One of the best experts on this subject based on the ideXlab platform.
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prenatal diagnosis of Exencephaly
Prenatal Diagnosis, 1993Co-Authors: M Casellas, M Ferrer, M Rovira, F Pla, M A Martinez, L CaberoAbstract:This paper presents a sonographic diagnosis of Exencephaly made during the last trimester of gestation. The sonogram showed the absence of bones in the cranial vault together with the presence of a disorganized cerebral mass, with loss of its normal anatomy. Post-partum examination of the newborn confirmed the findings of the sonogram. We briefly review the characteristics of Exencephaly, its aetiology, and its relationship to anencephaly.
R Padmanabhan - One of the best experts on this subject based on the ideXlab platform.
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effect of maternal methionine pre treatment on alcohol induced Exencephaly and axial skeletal dysmorphogenesis in mouse fetuses
Drug and Alcohol Dependence, 2002Co-Authors: R Padmanabhan, Ahmad Asrul Ibrahim, Abulbari BenerAbstract:Abstract Alcohol is known to induce folate deficiency and impair methionine synthase activity. Exogenous folic acid (FA) administered periconceptionally has been shown to prevent the first occurrence and recurrence of neural tube defects (NTD) in humans. Since folate, vitamin B 12 and methionine are metabolically interrelated, it was decided to determine the effect of methionine pre-treatment on alcohol-induced NTD and axial skeletal defects in mouse embryos. Following administration of a single dose of 70 or 150 mg/kg of methionine, 0.03 ml/g body weight of ethanol solution (25% v/v of absolute alcohol in saline) was injected intraperitoneally into pregnant mice at critical stages of neural tube development. The controls were either non-treated or saline treated and pair-fed and pair-watered. Fetuses were collected on gestation day 18. Alcohol and methionine plus alcohol numerically enhanced embryonic resorption and induced a significant reduction in fetal body weight. Alcohol alone caused a 3-fold increase in the background frequency of Exencephaly in gestation days 7 and 8 treatment groups. The low dose of methionine only numerically reduced the spontaneous Exencephaly. Pre-treatment with methionine only produced a numerical but not statistically significant reduction in alcohol-induced Exencephaly. The higher dose of methionine did not produce a particularly beneficial effect on embryonic survival, fetal body weight and occurrence of Exencephaly. Alcohol-induced cleft palate and limb malformations were ameliorated by methionine pre-treatment. Craniofacial skeleton, vertebrae and ribs were extensively malformed both in the alcohol and methionine plus alcohol groups indicating a lack of rescue effects of methionine. Whereas supernumerary ribs and extra sternal ribs were augmented by methionine, occipitalization of the atlas vertebra was a malformation unique to the pre-treatment group. Plasma levels of several amino acids including that of methionine were significantly lowered by alcohol. Pre-treatment with methionine produced a dose dependent enhancement of only methionine concentration. These data suggest that pre-administration of methionine only rescues mouse embryos of certain non-neural malformations and that the lack of ameliorative effect on NTD and axial skeletal defects may be due to the fact that alcohol lowers the concentration of a number of amino acids and therefore, supplementation should comprise a mixture of these amino acids and possibly FA and vitamin B 12 .
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Exencephaly and axial skeletal malformations induced by maternal administration of sodium valproate in the mf1 mouse
Journal of Craniofacial Genetics and Developmental Biology, 1994Co-Authors: R Padmanabhan, M S HameedAbstract:Abstract Clinical and epidemiological studies indicate that maternal use of valproic acid (VPA) during pregnancy causes an increased risk for spina bifida in the fetus. A proportion of infants exposed to VPA in utero exhibit a characteristic pattern of facial malformations. Despite the developmental interdependence of the neural plate and paraxial mesoderm during normal morphogenesis, the possible involvement of the axial skeleton in VPA-induced NTD has not been clearly documented. So the objective of this investigation was to determine the nature and extent of involvement of the axial skeleton in VPA-induced Exencephaly in the mouse. A single dose of 600 mg/kg of sodium valproate was administered (IP) to MF1 mouse on day 8 of gestation. This treatment resulted in significant increase in resorption, reduction in mean fetal weight, and Exencephaly (25%) of live fetuses. Several craniofacial malformations and subcutaneous haematomas were associated with Exencephaly. Alizarin red-stained skeletal preparations revealed maxillary-, mandibular hypoplasia, absence of skull vault, hypoplasia and/or agenesis of basicranial bones, and obtuse angulation of the craniovertebral junction. Hemivertebrae, longitudinal fusion of the vertebral arches and bodies, accessory ribs (cervical and lumbar), fusion of thoracic ribs, and several patterns of sternal variations were observed. Nonexencephalic VPA-treated embryos exhibited mandibular, maxillary hypoplasia, arched and cleft palates, cleft lip, kinky tail, and vertebral and sternal anomalies. Treated embryos at early stages of development revealed delay in elevation and fusion of neural folds, distended IVth ventricle, kinky spinal cord, incomplete separation of somites and growth retardation. When viewed in light of the published work on VPA action on embryonic systems, these observations suggest that abnormalities associated with VPA-induced Exencephaly may be due to either a direct action of VPA on the precursors of these organs or secondary to its action on neural tube. A significantly high incidence of NTD and their consistent association with defective development of the axial skeleton suggest that this is an excellent experimental model for investigating the pathogenetic mechanism(s) of VPA induced NTD.
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is Exencephaly the forerunner of anencephaly
Cells Tissues Organs, 1991Co-Authors: R PadmanabhanAbstract:Exencephaly is said to precede anencephaly resulting from failure of the rostral neuropore closure. In order to verify if the Exencephaly induced after neural tube closure would also lead to anencephaly, Exencephaly was induced in rat fetuses by maternal administration of a single dose (15 mg/kg) of cyclophosphamide on day 12 of gesta tion and pregnancy was prolonged by uterine ligation until postconception (PC) day 24. Fetal death was found to increase with prolongation of gestation and no sign of recovery from growth retardation was observed. Alizarin red-S stained skeletal preparations substantiated the persistence of skull malformations in the exencephalic fetuses. Histological observations of the mesenchyme and the brain indicated degenerative changes that were intensifying with time. The ventricular system expanded progressively; the ependyma was denuded and neural mass lay free in the ventricle. The choroid plexus appeared to be elaborate and extensive. The haemorrhagic capillary network around the brain tissue was highly proliferative and appeared to penetrate the former from the exterior. Tissue necrosis seemed to progress unabated. Cystic spaces appeared beneath the base of the brain and became progressively large and it appeared as if the brain was being pushed out of the shallow cranial fossae. By PC day 24, most of the brain tissue had degenerated, thus giving clearly the appearance of the anencephalic condition.