<i>Zfp423/ZNF423</i> regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors

Abstract

The <i>Zfp423/ZNF423</i> gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null <i>Zfp423</i> mutants develop cerebellar malformations, the underlying mechanism remains unknown. <i>ZNF423</i> mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. <i>ZNF423</i> participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize <i>in vivo</i> the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our <i>in vivo</i> evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies.