Mouse models for neural tube closure defects

Abstract

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.

Transcription factor TEAD2 is involved in neural tube closure

“…However, the NTD seen in Tead2 nullizygous mice contrasts with that observed in Pax3 nullizygous mice. Pax3 mutants not only exhibit complete penetrance of a NTD, but they exhibit both exencephaly and spina bifida aperta (Harris and Juriloff, 2007;Juriloff and Harris, 2000). The absence of a more severe phenotype in Tead2 nullizygous embryos reflects the fact that expression of Pax3 at E11.5 was not suppressed in embryos lacking Tead2 (Fig.…”

“…NTD, which includes anencephaly, appears in one out of one thousand births making it the most common form of birth abnormality in humans. Although specific mutations in mice can cause NTDs, multiple genes are thought to be involved in human NTDs (Juriloff and Harris, 2000). Therefore, the mouse models most relevant for clinical implications are those that exhibit incomplete penetrance .…”

“…Neural tube closure begins when the epithelial cells lining the neural folds "elevate," and fusion begins at four separate sites from the cranial to the caudal regions (Juriloff and Harris, 2000). Exencephaly results from failure of the cranial neuroepithelial cells to elevate at or near Closure 2.…”

Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

“…Cranial NTDs are also often associated with defective development of head mesenchyme (Juriloff and Harris, 2000;Copp et al, 2003). Both reduced and increased numbers of head (Chen and Behringer, 1995;Zhao et al, 1996).…”

Spatial and temporal expression of folate‐binding protein 1 (Fbp1) is closely associated with anterior neural tube closure in mice

“…The lateral edges of the neural plate elevate to form the neural folds and they fuse to form the neural tube. The fusion of the neural folds initiates at several sites in mammalian embryos, although the mode of neural tube closure may be different among species (Van Allen et al, 1993;Juriloff and Harris, 2000;Nakatsu et al, 2000).…”