Huwe1 ubiquitin ligase is essential to synchronize neuronal and glial differentiation in the developing cerebellum

We have generated a knockout mouse strain in which the gene coding for the ubiquitin ligase Huwe1 has been inactivated in cerebellar granule neuron precursors (CGNPs) and radial glia. These mice have a high rate of postnatal lethality and profound cerebellar abnormalities. The external granule layer of the cerebellum, which contains CGNPs, is expanded and displays aberrant proliferation and impaired differentiation of the progenitor cell population. The uncontrolled proliferation of the CGNPs is associated with accumulation of the N-Myc oncoprotein, a substrate of Huwe1, and consequent activation of the signaling events downstream to N-Myc. Furthermore, loss of Huwe1 in Bergmann glia leads to extensive disorganization of this cell population with layering aberrations, severe granule neuron migration defects, and persistence of ectopic clusters of granule neurons in the external granule layer. Our findings uncover an unexpected role for Huwe1 in regulating Bergmann glia differentiation and indicate that this ubiquitin ligase orchestrates the programming of the neural progenitors that give rise to neurons and glia in the cerebellum.