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.
The zinc finger transcription factor GLI3 is considered a repressor of vertebrate Hedgehog (Hh) signaling. In humans, the absence of GLI3 function causes Greig cephalopolysyndactyly syndrome, affecting the development of the brain, eye, face, and limb. Because the etiology of these malformations is not well understood, we examined the phenotype of mouse Gli3-/- mutants as a model to investigate this. We observed an up-regulation of Fgf8 in the anterior neural ridge, isthmus, eye, facial primordia, and limb buds of mutant embryos, sites coinciding with the human disease. Intriguingly, endogenous apoptosis was reduced in Fgf8-positive areas in Gli3-/- mutants. Since SHH is thought to be involved in Fgf8 regulation, we compared Fgf8 expression in Shh-/- and Gli3-/-;Shh-/- mutant embryos. Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH. In the limb bud, we provide evidence that ectopic expression of Gremlin in Gli3-/- mutants might contribute to a decrease in apoptosis. Together, our data reveal that GLI3 limits Fgf8-expression domains in multiple tissues, through a mechanism that may include the induction or maintenance of apoptosis.
Shh expression in PME cells is involved in the pathogenesis of ethanol-induced HPE. Ethanol may impair Shh expression indirectly by activating PKA. The inhibition of excessive apoptosis in PME cells by antioxidants implies that oxidative stress may underlie the teratogenic actions of ethanol. Thus, antioxidant treatment may be a simple preventative measure that could reduce the incidence of HPE following fetal ethanol exposure.
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