Phenotype of the neural tube defect mouse model bent tail is not sensitive to maternal folinic acid, <i>myo</i>‐inositol, or zinc supplementation

Franke, Barbara; Klootwijk, Riko; Lemmers, Bianca; Kovel, Carolien G.F. de; Steegers‐Theunissen, R.P.M.; Mariman, E.C.M.

doi:10.1002/bdra.10132

Cited by 8 publications

(7 citation statements)

References 38 publications

(47 reference statements)

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“…The percentage found in Bn matings was in accordance with the results of studies at later embryonic stages (Klootwijk et al 2000, and unpublished results), indicating that most of the resorbed embryos already died before ED10. The loss of embryos due to resorption appeared to be linked to the most affected genotypes generating a trend towards under-representation of Bn/Bn and Bn/Y genotypes, consistent with the results of other studies (Carrel et al 2000;Franke et al 2003).…”

Section: Discussionsupporting

confidence: 91%

Analysis of the embryonic phenotype of Bent tail, a mouse model for X-linked neural tube defects

Franke¹,

Klootwijk²,

Hekking

et al. 2003

Anatomy and Embryology

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Neural tube defects, mostly believed to result from closure defects of the neural tube during embryonic development, are frequently observed congenital malformations in humans. Since the etiology of these defects is not well understood yet, many animal models for neural tube defects, either arising from spontaneous mutations or generated by gene targeting, are being studied. The Bent tail mouse is a model for X-linked neural tube defects. This mutant has a characteristic short and kinked tail. Exencephaly occurs in Bent tail embryos with a frequency of 11-16%. Laterality defects also belong to the phenotypic spectrum. In this study, we analyzed the embryonic phenotype in further detail using scanning electron microscopy during the stages of neurulation. We observed a number of defects in both wild type and Bent tail embryos, including a kinked neural tube, tight amnion, delay in axial rotation and even malrotation. The severity or frequency of most defects, the delay in axial rotation excluded, was significantly higher in Bent tail embryos compared to wild type embryos. Other abnormalities were seen in Bent tail embryos only. These defects were related to anterior and posterior neural tube closure and resulted in exencephaly and a closure delay of the posterior neuropore, respectively. The exencephalic phenotype was further analyzed by light microscopy in ED14 embryos, showing disorganization and overgrowth in the mesencephalon and rhombencephalon. In conclusion, the anterior and posterior neural tube closure defects in the Bent tail are strictly linked to the genetic defect in this mouse. Other phenotypic features described in this study also occur in the wild type genetic background of the Bent tail strain. Apparently, the genetic background contains elements conducive to these developmental abnormalities.

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Section: Discussionsupporting

confidence: 91%

Analysis of the embryonic phenotype of Bent tail, a mouse model for X-linked neural tube defects

Franke¹,

Klootwijk²,

Hekking

et al. 2003

Anatomy and Embryology

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“…For example, cranial NTDs in the curly tail strain appear to largely be a feature of the genetic background as, unlike spina bifida, they are not prevented by transgenic reinstatement of Grhl3 expression (Sudiwala et al, 2016). Spinal closure defects in the Bent tail mouse, carrying an X chromosome deletion that encompasses Zic3 (Franke et al, 2003;Klootwijk et al, 2004), and in Mekk4 knockouts (Chi et al, 2005) were also found to be unresponsive to inositol treatment.…”

Section: Inositol Supplementation In Models Of Ntdsmentioning

confidence: 99%

Inositol, neural tube closure and the prevention of neural tube defects

Greene

Leung

Copp

2017

Birth Defects Research

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Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition. Maternal periconceptional supplementation with folic acid significantly reduces the risk of an NTD‐affected pregnancy, but does not prevent all NTDs, and “folic acid non‐responsive” NTDs continue to occur. Similarly, among mouse models of NTDs, some are responsive to folic acid but others are not.Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate‐deficiency induced NTD model. NTDs also occur in mice lacking expression of certain inositol kinases. Inositol‐containing phospholipids (phosphoinositides) and soluble inositol phosphates mediate a range of functions, including intracellular signaling, interaction with cytoskeletal proteins, and regulation of membrane identity in trafficking and cell division. Myo‐inositol has been trialed in humans for a range of conditions and appears safe for use in human pregnancy. In pilot studies in Italy and the United Kingdom, women took inositol together with folic acid preconceptionally, after one or more previous NTD‐affected pregnancies. In nonrandomized cohorts and a randomized double‐blind study in the United Kingdom, no recurrent NTDs were observed among 52 pregnancies reported to date.Larger‐scale fully powered trials are needed to determine whether supplementation with inositol and folic acid would more effectively prevent NTDs than folic acid alone. Birth Defects Research 109:68–80, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.

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“…It therefore appears that, depending on genetic, metabolic and environmental context, NTDs may be preventable by either FA, or inositol or both. On the other hand, there are several mutant strains that are non-responsive to either nutrient, including SELH/Bc, the Grhl3 null mutant, mutants for Zic2 and Zic3 [Franke et al, 2003], and MEKK4/ Map3k4-deficient mice [Chi et al, 2005]. …”

Section: Mechanisms and Mouse Models: Nutrient Modulation Of Neural Tmentioning

confidence: 99%

“…A second concern regarding diets is related to the finding that carbohydrate and fat content of the maternal diet [Rosenfeld et al, 2003] and type of polyunsaturated fatty acids [Fountain et al, 2008] can affect the sex ratio in progeny. Because [Marean et al, 2011] Tead2 folic acid resistant [Kaneko et al, 2007] Ski folic acid resistant [Ernest et al, 2006] Grhl3/curly tail inositol-deficiency t folate resistant [Cockroft et al, 1992;Tran et al, 2002] retinoic acid t [Chen et al, 1994] inositol t ] Grhl3 null folic acid and inositol resistant [Ting et al, 2003] Map3k4/MEKK4 folic acid and inositol resistant [Chi et al, 2005] Zic3/bent tail folic acid and inositol resistant [Franke et al, 2003] Increased resorptions and rate of neural tube defects, no effect on survival of particular genotypes. g Inositol supplementation significantly reduced survival of homozygotes and increased, among the survivors, the frequency of individuals with both exencephaly and spina bifida.…”

Section: Selh/bcmentioning

confidence: 99%

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Kappen¹

2013

American J of Med Genetics Pt C

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Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient–gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity.

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Phenotype of the neural tube defect mouse model bent tail is not sensitive to maternal folinic acid, myo‐inositol, or zinc supplementation

Abstract: Bent tail appears to be a folinic acid-, myo-inositol-, and zinc-insensitive mouse model for NTDs.

Cited by 8 publications

References 38 publications

Analysis of the embryonic phenotype of Bent tail, a mouse model for X-linked neural tube defects

Analysis of the embryonic phenotype of Bent tail, a mouse model for X-linked neural tube defects

Inositol, neural tube closure and the prevention of neural tube defects

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

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