Genesis and prevention of spinal neural tube defects in the curly tail mutant mouse: involvement of retinoic acid and its nuclear receptors RAR-β and RAR-γ

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Abstract
A role for all-trans-retinoic acid in spinal neurulation is suggested by: (1) the reciprocal domains of expression of the retinoic acid receptors RAR-β and RAR-γ in the region of the closed neural tube and open posterior neuropore, respectively, and (2) the preventive effect of maternally administered retinoic acid (5 mg/kg) on spinal neural tube defects in curly tail (ct/ct) mice. Using in situ hybridisation and computerised image analysis we show here that in ct/ct embryos, RAR-β transcripts are deficient in the hindgut endoderm, a tissue whose proliferation rate is abnormal in the ct mutant, and RAR-γ transcripts are deficient in the tail bud and posterior neuropore region. The degree of deficiency of RAR-γ transcripts is correlated with the severity of delay of posterior neuropore closure. As early as 2 hours following RA treatment at 10 days 8 hours post coitum, i.e. well before any morphogenetic effects are detectable, RAR-β expression is specifically upregulated in the hindgut endoderm, and the abnormal expression pattern of RAR-γ is also altered. These results suggest that the spinal neural tube defects which characterise the curly tail phenotype may be due to interaction between the ct gene product and one or more aspects of the retinoic acid signalling pathway.