Ethanol-kat6a interaction induces mandibular arch defects during craniofacial development



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Prenatal alcohol exposure can induce a variety of developmental defects characterized as “Fetal alcohol spectrum disorders” (FASD). FASD remains a significant health concern and yet little is known about the mechanism of alcohol-induced birth defects. These defects are often concentrated around the craniofacial region which are developed from transient structures called pharyngeal arches. This research aims to investigate how loss of one or both functional copy of the lysine acetyltransferase 6A (kat6a) gene can modulate the alcohol-induced craniofacial phenotype during zebrafish development. The kat6a gene is a chromatin modifier that regulates hox gene expression. The hox genes are expressed in the second and posterior-pharyngeal-arches but not in the first pharyngeal arch compartment. Thus, the zebrafish kat6a mutants exhibit second arch patterning defects, disrupting jaw support skeleton, while the jaw and palatal skeleton, derived from the first arch remains largely unaffected. However, when the developing embryos are exposed to ethanol, kat6a mutants also exhibit defects in the first pharyngeal arch skeletal elements. Measurements of pharyngeal arch elements in control versus ethanol-treated samples revealed significant shortening and often loss of first-pharyngeal arch elements in the ethanol-treated kat6a mutants and heterozygotes. Mutants were also exposed to ethanol at various developmental windows to determine the stage post-fertilization most susceptible to ethanol-induced effects. This revealed 10-24 hpf as the shortest exposure window which caused significant ethanol-induced effects . Furthermore, I also found that the lowest dose of ethanol that caused defects was 0.25% EtOH. Overall, my thesis demonstrates how an interplay between alcohol and kat6a can exacerbate craniofacial defects. This work also suggests a novel role of kat6a in the morphogenesis of the first pharyngeal arch. In the future, I aim to understand how the kat6a-alcohol interaction impacts cellular processes and gene expression patterns in the first pharyngeal arch during zebrafish development.


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