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 defect s in mice cause obvious risk of NTD, but most are syndromic and many a re lethal to embryos. Only a subset is similar to the common, nonsyndr omic, genetically complex spina bifida or anencephaly in humans. The n onsyndromic variants that are potentially good models include homozygo tes for spontaneous (Axd or Lp) or targeted (Apob, Mac;, Mrp, or Trp53 ) mutations and five strains with spontaneous NTD of genetically compl ex cause, i.e., curly tail, SELH/Bc, NZW-xid, MT/Hokldr, and TO. Curly tail (1-5% exencephaly, 15-20% spina bifida) and SELH/Bc (15-20% exen cephaly) are the best-understood developmental models for human spina bifida and anencephaly, but the genes are not yet known. The curly tai l and Cart1 gene ''knockout'' models show that the defect leading to N TD 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 closu re mechanism. The Splotch mutations have been the most studied syndrom ic 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 genetica lly distinct models, each of which responds to a different nutrient. A s in human anencephalics, an excess of females among exencephalics (of between 2-20-fold) is observed in seven mouse NTD genetically distinc t models. Generally, strains with spontaneous NTD have a relatively hi gh risk of NTD after exposure to the human teratogens, valproic acid, or retinoids. Nonsyndromic NTD in mice are genetically heterogeneous a nd often genetically complex, and we predict a similar genetic heterog eneity in human NTD. The genes contributing to the genetically complex NTD in mice, when identified, will provide candidate genes to test fo r association with human NTD risk. (C) 1998 Wiley-Liss, Inc.