The use of mouse models to elucidate the genetic and environmental components of neural tube defects

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 88-108).Neural tub defects (NTDs) rank among the most common phics. congenital anomalies affecting human infants worldwide. Unfortunately, the: etiology is poorly understood accuse the genetic and environmental components contributing to their expression are extremely complex. Inbred mouse strains are highly regarded as animal models for studying the etiology of NTDS because their genetics are so well characterized and there is a high degree of homology between human and murine genomes. Furthermore, it is thought that murine neuruation follows a pattern very similar to that of humans. Two of the more popular murine models for the study of NTDS are the Splotch and curly-tail mutant mice. We used curly-tail mice to examine the genetic factors contributing to spinal ' NTDS. The nGNA levels of genes implicated in the curly-tail phenotype, as well as other candidate genes for NTDS, were quantified over five timepoints during neurulation by RT/aRNA amplification. Our observations confirm a role for [] and [] CT spinal NTDS and identify a new genetic factor contributing to these defects, TGF-R. To otter clarify the impact of environmental factors on NTDS, Splotch mice were used to examine the role of supplemental folate on the induced NTDS. Two forms of notate, folic acid and folinic acid, were examined. Folic acid or folinic acid administered alone did not ameliorate the incidence of spontaneous NTDS in Splotch mice. Folic acid protected against arsenic-induced NTDS by selective resolution of affected conceptuses, while folic acid induced lethality in arsenic treated animals

Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development

Neural tube defects (NTDs) are prevalent human birth defects. Mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK), are implicated in facilitating neural tube closure, yet upstream regulators remain to be identified. Here, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepithelium. Mice deficient in MEKK4 develop highly penetrant NTDs that cannot be rescued by supplementation with folic acid or inositol. Unlike most mouse models of NTDs, MEKK4 mutant embryos display genetically co-segregated exencephaly and spina bifida, recapitulating the phenotypes observed in human patients. To identify downstream targets of MEKK4 during neural tube development, we examined the activity of MAP kinase kinase 4 (MKK4), a signaling intermediate between MAP kinase kinase kinase and JNK/p38. We found a significant reduction in MKK4 activity in MEKK4-deficient neuroepithelium at sites of neural tube closure. MAPK pathways are key regulators of cell apoptosis and proliferation. Analyses of the neuroepithelium in MEKK4-deficient embryos showed massively elevated apoptosis before and during neural tube closure, suggesting an antiapoptotic role for MEKK4 during development. In contrast, proliferation of MEKK4-deficient neuroepithelial cells appeared to be largely unaffected. MEKK4 therefore plays a critical role in regulating MKK4 activity and apoptotic cell death during neural tube development. Disruption of this signaling pathway may be clinically relevant to folate-resistant human NTDs

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