Journal
NATURE MEDICINE
Volume 14, Issue 2, Pages 125-133Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1725
Keywords
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Funding
- Medical Research Council [G0400264] Funding Source: Medline
- NIDCR NIH HHS [R01 DE016082-06, P50 DE 016215, R01 DE016082-04, R01 DE016082-03, P50 DE016215, R01 DE016082-05, R01 DE 016082-01, R01 DE016082-02, R01 DE016082, R01 DE016082-01] Funding Source: Medline
- Medical Research Council [G0400264] Funding Source: researchfish
- MRC [G0400264] Funding Source: UKRI
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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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