KAT3 mutations impair neural crest migration through EMT regulatorssnai1b andsnai2in Rubinstein Taybi Syndrome

Abstract

Rubinstein Taybi syndrome, a rare congenital disease is caused by mutation in KAT3 genes, EP300 and CREBBP. A subset of tissues affected in RSTS have their origin in neural crest cells, prompting our exploration into the role of KAT3 in neural crest development. Our zebrafish RSTS models generated by knocking down or mutating ep300a and cbpa genes, reveal defects in neural crest migration and its derived tissues when KAT3 genes are perturbed. We also demonstrate that the effects on neural crest can be reversed by HDAC inhibition in in morphant embryos. KAT3 knockdown causes downregulation of EMT regulators, snai1b and snai2. Snai2 is known to repress cdh6b in neural crest cells facilitating their delamination from neural tube and migration. We generated RSTS patient-derived iPSC line and differentiated them into neural crest cells in vitro. We show that role of KAT3 proteins in neural crest migration is conserved in human iPSC derived neural crest cells. Our findings make a case for classifying RSTS as a neurocristopathy.