Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function

Abstract

Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1–mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1–driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.

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Figure 1: Immunoblot analysis of p53.
Figure 2: Immunostaining of p53.
Figure 3: Expression of Ccng1 and inhibition of apoptosis.
Figure 4: Analyses of apoptosis and ribosome biogenesis.
Figure 5: Embryonic skeletal analyses and prevention of TCS.
Figure 6: Genetic prevention of postnatal TCS craniofacial anomalies.

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Acknowledgements

We thank the Trainor and Dixon groups for comments on the manuscript; R. McCay and M. Morgan for maintenance of mutant mouse lines and administration of pifithrin-α; T. Yao and J. Ren for technical assistance with protein analysis and p53 antibody activity; D. Stark for confocal imaging expertise; S. Das for the Ccng1 riboprobe, D. Quelle and M. Horne for Ccng1 expression vectors; and E. Rubel for the Y10b antibody. Research in the Trainor laboratory is supported by the Stowers Institute for Medical Research, March of Dimes (6FY05-82), National Institute of Dental and Craniofacial Research (RO1 DE 016082-01) and the Hudson Foundation. Research in the Dixon laboratory is supported by the National Institutes of Health (P50 DE 016215) and the Medical Research Council, UK (G81/535).

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N.C.J., J.D., M.J.D. and P.A.T. conceived and designed the project and wrote the manuscript. N.C.J., M.L.L. and L.E. performed embryonic skeletal and adult analyses; N.C.J., K.G. and E.F.G. performed microarray and quantitative PCR analyses; N.C.J., M.L.L. and P.A.T. performed in situ hybridization and TUNEL staining; N.C.J., D.S., K.A. and J.-P.R. performed immunohistochemistry; D.S. performed electroporation and C.D., J.D. and M.J.D. provided knockout mice and other reagents.

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Correspondence to Paul A Trainor.

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Supplementary Table 1 and Supplementary Figs. 1–7 (PDF 581 kb)

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Jones, N., Lynn, M., Gaudenz, K. et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med 14, 125–133 (2008). https://doi.org/10.1038/nm1725

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