Human Molecular Genetics Advance Access originally published online on November 13, 2007
Human Molecular Genetics 2008 17(4):587-601; doi:10.1093/hmg/ddm333
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Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube
1 Center for Environmental and Genetic Medicine 2 Center for Molecular Development and Disease, Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030, USA 3 Texas Institute for Genomic Medicine, 2121 W. Holcombe Blvd, Houston, TX 77030, USA 4 Department of Pharmaceutical Biology 5 Department of Biotherapeutics 6 Department of Genetics, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA
* To whom correspondence should be addressed at: Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030, USA. Tel: +1 7136777667; Fax: +1 7136777784; Email: lwong{at}ibt.tamhsc.edu
Received October 4, 2007; Accepted November 9, 2007
Neural tube defects (NTDs) are birth defects that can be disabling or lethal and are second in their prevalence after cardiac defects among major human congenital malformations. Spina bifida is a NTD where the spinal cord is dysplastic, and the overlying spinal column is absent. At present, the molecular mechanisms underlying the spinal bifida development are largely unknown. In this study, we present a Fkbp8 mouse mutant that has an isolated and completely penetrant spina bifida, which is folate- and inositol-resistant. Fkbp8 mutants are not embryo lethal, but they display striking features of human spina bifida, including a dysplastic spinal cord, open neural canal and disability. The loss of Fkbp8 leads to increased apoptosis in the posterior neural tube, demonstrating that in vivo FKBP8 inhibits cell death. Gene expression analysis of Fkbp8 mutants revealed a perturbation of expression of neural tube patterning genes, suggesting that endogenous FKBP8 activity establishes dorso-ventral patterning of the neural tube. These studies demonstrate that Fkbp8 is not important for embryo survival, but is essential for spinal neural tube patterning, and to block apoptosis, in the developing neural tube. The mutant Fkbp8 allele is a new experimental model which will be useful in dissecting the pathogenesis of spinal NTDs, and enhance our understanding of the etiology of human NTDs.