Mutations in KAT3 family of lysine acetyl transferases impair neural crest migration in Rubinstein Taybi syndrome models

BACKGROUND: Rubinstein Taybi syndrome (RSTS), a rare congenital disease, is caused by mutations in lysine acetyl transferase type 3 (KAT3) genes, EP300 and CREBBP. Many of the tissues affected in RSTS are derived from the neural crest (NC). Hence, we proposed that NC development would be perturbed in RSTS. RESULTS: Zebrafish RSTS models generated by knocking down or mutating ep300a and crebbpa genes reveal defects in NC migration. This effect on migration is conserved in NC cells generated from human RSTS patient-derived induced pluripotent stem cells (iPSC) cells. The defects in NC migration can be partially reversed by HDAC inhibition in morphant embryos. KAT3 knockdown causes downregulation of snai1b and snai2 and upregulation of cdh6, important regulators of epithelial to mesenchymal transition (EMT). Snai2 is known to repress CDH6, also known as cadherin 6b, in chick NC cells facilitating their delamination from the neural tube and migration. CONCLUSIONS: We demonstrate for the first time that NC migration is defective in zebrafish and iPSC models of RSTS. We make a case for classifying RSTS as a neurocristopathy. We propose that KAT3 genes control NC migration through regulation of EMT genes snai2 and snai1b.