Elevated levels of ZAC1 disrupt neurogenesis and promote rapid in vivo reprogramming

• High ZAC1 levels disrupt neurogenesis and promote in vivo myogenic reprogramming.
• Elevated ZAC1 levels induce expression of genes regulating pluripotency.
• ZAC1 induced cell cycle exit but not reprogramming is dependent on P57.
• Zac1 expression is negatively regulated by SOXB1 transcription factors.

The zinc finger transcription factor Zac1 is expressed in dividing progenitors of the nervous system with expression levels negatively controlled by genomic imprinting. To explore the consequences of elevated ZAC1 levels during neurogenesis we overexpressed it in the developing CNS. Increased levels of ZAC1 rapidly promoted upregulation of CDK inhibitors P57 and P27 followed by cell cycle exit. Surprisingly this was accompanied by stalled neuronal differentiation. Genome wide expression analysis of cortical cells overexpressing Zac1 revealed a decrease in neuronal gene expression and an increased expression of imprinted genes, factors regulating mesoderm formation as well as features of differentiated muscle. In addition, we observed a rapid induction of several genes regulating pluripotency. Taken together, our data suggests that expression levels of Zac1 need to be kept under strict control to avoid premature cell cycle exit, disrupted neurogenesis and aberrant expression of non-neuronal genes including pluripotency associated factors.