Mini-review: Toward understanding mechanisms of genetic neural tube defects in mice

We review the data from studies of mouse mutants that lend insight to the m echanisms that lead to neural tube defects (NTDs). Most of the 50 single-ge ne mutations that cause neural tube defects (NTDs) in mice also cause sever e embryonic-lethal syndromes, in which exencephaly is a nonspecific feature . In a few mutants (e.g., Trp53, Macs, Mlp or Sp), other defects may be pre sent, but affected fetuses can survive to birth. Multifactorial genetic cau ses, as are present in the curly tail stock (15-20% spina bifida), or the S ELH/Bc strain (15-20% exencephaly), lead to nonsyndromic NTDs. The mutation s indicate that "spina bifida occulta," a dorsal gap in the vertebral arche s over an intact neural tube, is usually genetically and developmentally un related to exencephaly or "spina bifida" (aperta). Almost all exencephaly o r spina bifida aperta of genetic origin is caused by failure of neural fold elevation. The developmental mechanisms in genetic NTDs are considered in terms of distinct rostrocaudal zones along the neural folds that likely dif fer in mechanism of elevation. Failure of elevation leads to: split face (z one A), exencephaly (zone B), rachischisis (all of zone D), or spina bifida (caudal zone D). The developmental mechanisms reading to these genetic NTD s are heterogeneous, even within one zone. At the tissue level, the mutants show that the mechanism of failure of elevation can involve, e.g., (1) slo w growth of adjacent tethered tissue (curly tail), (2) defective forebrain mesenchyme (Cart1 or twist), (3) defective basal lamina in surface ectoderm (Lama5), (4) excessive breadth of floorplate and notochord (Lp), (5) abnor mal neuroepithelium (Apob, Sp, Tcfap2a), (6) morphological deformation of n eural folds (jmj), (7) abnormal neuroepithelial and neural crest cell gap-j unction communication (Gja1), or (8) incomplete compensation for a defectiv e step in the elevation sequence (SELH/Bc). At the biochemical level, mutan ts suggest involvement of: (1) faulty regulation of apoptosis (Trp53 or p30 0), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimi dine synthesis (Sp). The NTD preventative effect of maternal dietary supple mentation is also heterogeneous, as demonstrated by: (I) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterog eneity of mechanism of mouse NTDs suggests that human NTDs, including the c ommon nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsi ble for elevation of the neural folds. (C) 1999 Wiley-Liss,Inc.