Modeling human intellectual disability and autism: role of the chromatin regulator setd5 during zebrafish brain development

SETD5 loss-of-function (LoF) mutations have been recently associated to intellectual disability (ID) and autistic spectrum disorders. Interestingly, SETD5 gene encodes for a putative histone H3 methyltransferase highly expressed in the brain and it falls within the critical interval deleted in the 3p25.3 microdeletion syndrome, characterized by ID, microcephaly and congenital heart defects. The aim of this study is to generate and characterize zebrafish models in which setd5 has been knocked down or knocked out. Antisense morpholino oligonucleotides-mediated targeting of setd5 in zebrafish embryos determined microcephaly, cardiac edema and reduced locomotory response. Compared to embryos injected with a control morpholino, setd5 LoF brains, despite their reduced size, show an increase of phospho-H3-positive mitotic cells, while neuronal differentiation marker HuC is not changed. We are currently evaluating whether phospho-H3 increase in setd5 morphants could be actually associated with a possible mitotic arrest, responsible of the increased apoptotic rate in developing brain areas. Furthermore, we are establishing stable setd5 knockout zebrafish lines through Crispr/Cas9 strategy. These animal models will be extremely useful to identify the molecular mechanisms underlying SETD5 LoF phenotype and to screen for compounds able to rescue the developmental defects.