Human Molecular Genetics Advance Access published online on November 13, 2007
Human Molecular Genetics, 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, Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030, USA 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, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA 5 Department of Biotherapeutics, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA 6 Department of Genetics, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA
* To whom correspondence should be addressed. Rebecca Lee Yean Wong, 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: +1 713 677 7667; Fax: +1 713 677 7784; Email: lwong{at}ibt.tamhsc.edu
Received October 4, 2007; Revised November 9, 2007; Accepted November 9, 2007
Neural tube defects (NTDs) are birth defects that can be disabling or lethal and are second only to cardiac defects in their prevalence 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 mouse Fkbp8 mutant that has an isolated and completely penetrant spina bifida, which is folate- and inositol-resistant. Fkbp8 mutants are not embryo-lethal, and they display striking features of human spina bifida including a dysplastic spinal cord, open neural canal, and disability. 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.
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