Characterization of a hypomorphic allele of the FKBP8 gene
Spina bifida is the most frequently occurring neural tube defect (NTD), affecting 1 per 1000 newborns in the US. NTDs are multifactorial, involving as yet poorly understood genetic and environmental factors. Our appreciation of their developmental pathology has benefited from experimental data obtained using mouse models. Here we describe a novel NTD mouse model which has 100% penetrance of the spina bifida phenotype. This genetically modified mouse model was generated using a gene trap inserted into the first intron of the FKBP8 gene, which leads to disrupted processing of its first two transcripts while leaving the last two transcripts unaffected. The previously described null mutation of FKBP8, having all transcripts knocked out, results in embryonic lethality by E13.5. The nullizygous fetuses presented with ocular and dorsal root ganglia defects. On the level of gene expression, there was also ectopic activation of the SHH pathway components, suggesting that FKBP8 may function as a negative regulator in this pathway. In our new FKBP8 mutant model, the nullizygous embryos are morphologically similar to normal embryos at E9.5, but exhibit a dilated posterior neural tube at E10.5. The neural tube is closed; however, cross-sectioned neural tubes revealed that the thickness of the neural tube is only 25-30% of the thickness observed in sections from control embryos. At E18.5, the nullizygous pups consistently present with spina bifida aperta in the thoracic-lumbar region. Alizarin staining revealed numerous abnormalities in the vertebrae, predominantly in the thoracic-lumbar region. These mice survive several weeks post-partum. Folate supplementation to FKBP8 dams failed to rescue the spina bifida phenotype. We believe this mouse represents a unique spina bifida model which will provide further insight into the etiology of NTDs.