Cellular and Molecular Mechanisms of FASD
Recent work from our lab has begun to investigate the impact of prenatal alcohol exposure on the structure and function of hair-like organelles called primary cilia. Cilia are found on almost every cell in the body and play a critical role in the transduction of morphogenic signaling pathways, such as Shh, during embryonic development. Genetic ciliopathies often present with phenotypes similar to those associated with heavy prenatal alcohol exposure, such as hypertelorism, polydactyly, microcephaly, and holoprosencephaly. Our lab uses both in vivo and in vitro techniques to uncover how alcohol affects primary cilia during early gestation and the consequences of alcohol-cilia interactions on the development of craniofacial and brain malformations and adolescent behavior.
Another potential mechanism of alcohol’s actions throughout development is apoptosis. We know that alcohol can induce apoptosis in some embryonic cells and that we can mostly prevent the effects of alcohol by knocking out key apoptotic genes (e.g. Bax). However, we do not currently understand exactly how alcohol induces apoptosis in some cell populations, but not others. An extensive area of interest in our lab is trying to understand these basic cellular mechanisms of alcohol’s actions during early embryonic development. We use a variety of in vivo and in vitro techniques to attempt to elucidate these mechanisms.
Genetics of FASD
Prenatal alcohol exposure does not affect all individuals in the same way – but why? A variety of factors, such as nutrition and alcohol metabolism, can influence how the offspring is affected by alcohol. Both twin studies and experiments comparing strain differences in animal models of FASD have shown that genetic variability is an important factor in determining an individual’s sensitivity to prenatal alcohol exposure. One of the goals of our lab, in collaboration with researchers in CIFASD, is to understand how baseline genetic variability can impact which gene networks are altered by prenatal alcohol. We use whole transcriptome sequencing (RNA-seq) to compare the expression of genes in closely-related mouse strains before and after alcohol exposure. To further probe the contribution of single genes/gene pathways in determining risk and resilience, we use multiple transgenic mouse lines with mutations or knockouts of genes important for regulation of apoptosis, the Sonic hedgehog (Shh) pathway, or primary cilia function. These experiments demonstrate that manipulation of specific molecular pathways can either increase the incidence and severity of alcohol-induced birth or provide protection against the damaging effect of alcohol.