Animal models of neural tube defects

We reviewed the genetic variants and strains of mice that are used as models for neural tube defects (NTD) in humans. Over 40 genetic defects in mice cause obvious risk of NTD, but most are syndromic and many are lethal to embryos. Only a subset is similar to the common, nonsyndromic, genetically complex spina bifida or anencephaly in humans. The nonsyndromic variants that are potentially good models include homozygotes for spontaneous (Axd or Lp) or targeted (Apob, Macs, Mrp, or Trp53) mutations and five strains with spontaneous NTD of genetically complex cause, i.e., curly tail, SELH/Bc, NZW-xid, MT/HokIdr, and TO. Curly tail (1–5% exencephaly, 15–20% spina bifida) and SELH/Bc (15–20% exencephaly) are the best-understood developmental models for human spina bifida and anencephaly, but the genes are not yet known. The curly tail and Cart1 gene “knockout” models show that the defect leading to NTD may be in the supporting tissues, and not in the neural tube itself. The SELH/Bc model shows that there are compensatory mechanisms that can close the neural tube despite genetic deficiency of a normal closure mechanism. The Splotch mutations have been the most studied syndromic NTD in mice and are now known to be Pax3 gene mutations that model human Waardenberg syndrome, not common NTD. Heterogeneity of effective nutritional approaches to prevention is demonstrated by five genetically distinct models, each of which responds to a different nutrient. As in human anencephalics, an excess of females among exencephalics (of between 2–20-fold) is observed in seven mouse NTD genetically distinct models. Generally, strains with spontaneous NTD have a relatively high risk of NTD after exposure to the human teratogens, valproic acid, or retinoids. Nonsyndromic NTD in mice are genetically heterogeneous and often genetically complex, and we predict a similar genetic heterogeneity in human NTD. The genes contributing to the genetically complex NTD in mice, when identified, will provide candidate genes to test for association with human NTD risk. MRDD Research Reviews 1998;4:254–263. © 1998 Wiley-Liss, Inc.