PREVENTION OF SPINAL NEURAL-TUBE DEFECTS IN THE CURLY TAIL MOUSE MUTANT BY A SPECIFIC EFFECT OF RETINOIC ACID

Curly tail mouse mutant embryos (ct/ct) develop spinal neural tube def ects (NTD) in 54% of cases, comprising isolated tail flexion defects a nd spina bifida with tail flexion defects. Both types of spinal NTD re sult from delayed closure of the posterior neuropore (PNP). Previous s tudies (Seller et al. [1979] Proc. R. Sec. Lend. Biol. 206:95-107; Sel ler and Perkins [1982] Prenat. Diagn. 2:297300) described a paradoxial effect of retinoic acid (RA) on the phenotypic expression of the ct m utation: Treatment with low doses of RA on day 8 of gestation increase d the incidence of total NTD, whereas low doses of RA administered on day 9 resulted in reduced incidence of total NTD. In order to investig ate further the reported preventive effect of RA, we have carried out detailed analyses of the effects of maternal treatment with 5 mg/kg RA on the incidence of NTD at different developmental stages, and on the development and growth of ct/ct embryos. We found that 5 mg/kg RA red uces the incidence of spinal NTD in a stage-specific manner, without i ncreasing the incidence of cranial NTD. The effect of RA is specific: There were no other alterations in morphogenesis, growth, development, resorption rate, or litter size. RA was more effective in the prevent ion of isolated tail flexion defects than of spina bifida. Prevention of isolated tail flexion defects was maximal (50% reduction) when RA w as administered between 10 days 4 hours and 10 days 8 hours post coitu m (p.c.) inclusive (24 to 34 somite stage). In contrast, maximal preve ntion of spina bifida (36%) resulted from RA administration at 10 days 8 hours p.c.; decreased PNP size in treated embryos, compared with co ntrol embryos, was evident by 6 hours after the treatment at the 27 to 31 somite stage. The preventive effect of RA on spina bifida was rela ted to maternal phenotype: By comparison with phenotypically straight- tailed mothers, curly-tailed mothers had a greater incidence of spina bifida among their offspring, and this incidence was unresponsive to R A. This result suggests that additional factors, such as modifier gene s, modulating phenotypic expression of the ct gene, may be present in the ct mutant stock. Here we show that the RA prevention of spinal NTD is a specific effect. Hence it is plausible that this prevention of s pinal NTD by RA is mediated via nuclear retinoic acid receptors. (C) 1 994 Wiley-Liss, Inc.