Abstract
Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1, no clear genotype–phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1+/− mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies.
Highlights
Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality
Considerable effort needs to be invested in developing therapeutic avenues for prevention, but this can only come from a better understanding of the genetic and cellular mechanisms that regulate neural crest cell development in association with the etiology and pathogenesis of individual malformation syndromes
Treacher Collins syndrome (TCS) is a rare disorder of craniofacial development, which is caused at the cellular level by a deficiency in the formation and survival of neural crest cells
Summary
Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Genetic and pharmacological inhibition of p53 can suppress neuroepithelial apoptosis in Tcof[1] þ / À embryos and prevent the pathogenesis of craniofacial anomalies characteristic of TCS7 This rescue occurs without restoration of ribosome biogenesis, implying that Tcof1/Treacle may play important roles in neuroepithelial cell and neural crest cell survival in addition to, and distinct from, its currently recognized function in ribosome biogenesis. Tcof1/Treacle associates with the MRNM complex (MRE11, Rad[51], NBS1 and MDC1) and functions in DNA damage response/repair to limit oxidative stress induced, neuroepithelial cell death, during early embryogenesis. Consistent with this idea, maternal antioxidant supplementation can ameliorate the pathogenesis of craniofacial abnormalities characteristic of TCS. In addition to its role in ribosome biogenesis, Tcof[1] may be required for protection of the neuroepithelium from oxidative stress-induced cell death
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