Kat6a functions to protect lower jaw patterning during cellular stress

Phenotypic outcomes of most birth defects involve complex multifactorial interactions. In humans, heterozygosity for KAT6A or MEF2C causes highly variable syndromes1,2. These syndromes overlap phenotypically with Fetal Alcohol Syndrome (FAS)2,3,4, with defects to the pharyngeal arches-derived craniofacial skeleton. In zebrafish, we demonstrate that cellular stressors, like ethanol, induce ventral patterning defects specifically in the first pharyngeal arch in kat6a mutants and heterozygotes and result in lower jaw defects. This is striking as anteroposterior and dorsoventral patterning of pharyngeal arches are typically independent. Kat6a regulates hox gene expression for anteroposterior patterning. Bmp/Edn1 signaling and their targets, like dlx genes and hand2, regulate dorsoventral patterning. In exposed kat6a mutants and heterozygotes, Bmp/Edn1 signaling remains intact. However, exposure causes a first arch specific loss of ventral specifiers in mutants and heterozygotes. The overall phenotype resembles loss of mef2ca, which governs dorsoventral patterning independent of Bmp/Edn1. We find that mef2ca is selectively lost in the first pharyngeal arch of exposed kat6a mutants and heterozygotes. CRISPR knockdown of mef2ca phenocopies the effect of exposure in kat6a mutants and heterozygotes. Tissue mosaics confirmed that first arch neural crest specifically require kat6a. Thus, multifactorial interactions reveal an unknown link between pharyngeal arch anteroposterior and dorsoventral patterning.