The Zfp423/ZNF423 gene encodes a 30-Zn-finger transcription factor involved in key developmental pathways. While null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations have been associated to Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA damage response, raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo 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 one impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DNA-damage response markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo 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 DNA damage response may be a key factor in the pathogenesis of JS and other ciliopathies.