The function of mTORC1 in craniofacial morphogenesis and ethanol teratogenesis

The mTOR pathway is a critical regulator of cell growth, cell survival, and autophagy. Over the last decade, there has been growing evidence suggesting that the mTOR pathway plays an essential role in craniofacial development. My research seeks to characterize the precise mechanisms by which this pathway functions during craniofacial development, as well as the downstream effects of its dysregulation. At the same time, prenatal ethanol exposure has long been known to cause a range of birth defects, including those affecting the craniofacial region. While the precise mechanisms by which ethanol exerts its teratogenic effects are still not fully understood, nearly all of the known mechanisms are regulated by the mTOR pathway. My research aims to characterize the role of the mTOR pathway in craniofacial development and to gain insight into the teratogenic effects of ethanol. Here, I utilized a zebrafish tp53 mutant which is deficient in inducing cell death and normally functions downstream of mTOR. I demonstrated that alcohol-induced reductions of eye size and trabecula length were less common and less severe in tp53 mutants, indicating a protective effect of tp53 deletion. This work, along with that of our collaborators using a mouse model, established that Tp53 plays a conserved role in prenatal ethanol exposure-induced cell death. I followed up this work by characterizing the role of mTORC1 in craniofacial development, by generating a zebrafish raptor mutant, an essential component of the complex. The raptor mutants exhibited a severe reduction in the size of craniofacial elements. I observed that this size reduction was attributed to reduced cell size and elevated cell death. Furthermore, I demonstrated that autophagy was elevated in raptor mutants, and that inhibition of autophagy reduced cell death and increased craniofacial element size. The findings of these studies have important implications for understanding the molecular and cellular processes that underlie craniofacial development and for developing new strategies to prevent and treat craniofacial abnormalities caused by the combinatorial effects of genetic mutations and environmental toxicants such as ethanol exposure.Cellular and Molecular Biolog