# Craniofacial Morphogenesis in Prenatal Alcohol Exposure

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $115,928

## Abstract

ABSTRACT
Prenatal alcohol exposure (PAE) remains a leading cause of permanent neurodevelopmental disability.
Diagnosis is often initiated by a distinctive craniofacial appearance that originates, in part, from the apoptotic
deletion of craniofacial progenitors, a stem cell lineage called the Neural Crest. In the prior award period, our
transcriptome analysis revealed that gene clusters mediating Ribosome Biogenesis (RBG; 70 genes, all
repressed) and Oxidative Phosphorylation (OxP; 60 genes, all repressed) exhibited the greatest differential
expression 6hr following transient alcohol exposure (52mM, 90min). These gene clusters also had the greatest
altered expression in genetic lineages of neural crest having differential vulnerability to alcohol, and
haploinsufficiency in RBG sensitized neural crest to alcohol-induced apoptosis and facial deficits. Here, we test
the hypothesis that disruption of RBG is mechanistic in alcohol's facial dysmorphology. Aim 1 shows that
alcohol reduces RBG and causes a nucleolar stress which then activates MDM2/p53-mediated apoptosis in
neural crest. Aim 2 shows this loss of RBG is due to alcohol's inactivation of mTORC1 and p70/S6K activity,
which are the major transcription-level stimulators of RBG. Aim 3 shows that alcohol inactivates mTORC1
because it depresses mitochondrial OxP and ATP generation and thus activates AMPK, which is a direct
repressor of mTORC1. We will also test a role for canonical Wnt/β-catenin signaling, which indirectly
stimulates RBG via TSC2 and is repressed by alcohol as we showed in the previous award period. Because
RBG consumes ~80% of total ATP generation in rapidly dividing cells like neural crest, cells have coopted
RBG to monitor their internal stress and have linked it to the p53-checkpoint pathway. In humans, impaired
RBG is now understood to underlie a family of genetic syndromes featuring facial anomalies with similarities to
those of FASD; these ribosomopathies cause the p53-mediated deletion of neural crest progenitors and are
rescued by TORC1 activation. Studies in this proposal test the novel hypothesis that the facial deficits in FASD
represent a ribosomopathy and establish the mechanism by which alcohol initiates the pro-apoptotic nucleolar
stress in neural crest progenitors.

## Key facts

- **NIH application ID:** 10529080
- **Project number:** 3R01AA011085-26S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** SUSAN M. SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $115,928
- **Award type:** 3
- **Project period:** 1996-07-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10529080

## Citation

> US National Institutes of Health, RePORTER application 10529080, Craniofacial Morphogenesis in Prenatal Alcohol Exposure (3R01AA011085-26S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10529080. Licensed CC0.

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