Cell cycle regulation in Fetal Alcohol Spectrum Disorders

Project Summary
Fetal Alcohol Spectrum Disorders (FASD) affects up to 5% of live births in the US each year and results in life-
long physical, cognitive, and behavioral impairments. Alcohol exposure during neurulation, the formation and
closure of the neural tube (~ 4th week of pregnancy in humans, gestational days 8-10 in mice), is associated
with abnormal growth of midline structures, such as the cortex, septum, pituitary, and ventricles, and
neurofunctional changes later in life. My preliminary work suggested that neurulation-stage alcohol causes cell
cycle arrest or delayed cell cycle progression, resulting in disrupted proliferation and, ultimately, anomalous
tissue and organ development. Specifically, we performed whole transcriptome profiling of the rostroventral
neural tube 6 hr after alcohol exposure and found that many genes and gene networks related to cell cycle
regulation and cell proliferation were altered by alcohol. In addition, neurulation-stage alcohol caused
significant dysregulation of the sonic hedgehog (Shh) pathway and cell cycle genes. These changes in
morphogenic signaling were concomitant with smaller rostral neural tube volumes and fewer actively dividing
cells in alcohol-exposed embryos. In this proposal, we use a well-characterized mouse model of FASD to test
the hypothesis that neurulation-stage alcohol exposure alters cell cycle regulation in the rostral neural tube
through disruption of processes that regulate cell cycle progression. Aim 1 analyzes cell cycle arrest and G1-
specific processes in the neural tube following prenatal alcohol. Preliminary data suggest dysregulation of
molecular mechanisms that control the successful transition between cell cycle stages and the DNA damage
response, possibly leading to impaired DNA integrity and replication errors. Aim 2 investigates pathways that
control protein degradation and trafficking during the cell cycle, following up on previous work showing
downregulation of genes encoding ubiquitylation enzymes by prenatal alcohol. Finally, Aim 3 examines
epigenetic marks associated with chromatin that regulate cell cycle progression, as pathways related to
chromatin modifications were found to altered by neurulation-stage alcohol in our preliminary studies. These
experiments will provide evidence that mechanisms of cell cycle progression represent an under-studied
pathway through which prenatal alcohol causes symptoms of FASD.

Grant Number: 5R00AA028273-05
NIH Institute/Center: NIH
Principal Investigator: Karen Boschen