Huwe1 ubiquitin ligase is essential to synchronize neuronal and glial differentiation in the developing cerebellum
Open Access
- 15 March 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (13), 5875-5880
- https://doi.org/10.1073/pnas.0912874107
Abstract
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 con-sequent 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 Berg-mann 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.Keywords
This publication has 42 references indexed in Scilit:
- The N-Myc-DLL3 Cascade Is Suppressed by the Ubiquitin Ligase Huwe1 to Inhibit Proliferation and Promote Neurogenesis in the Developing BrainDevelopmental Cell, 2009
- Neuron-derived FGF9 is essential for scaffold formation of Bergmann radial fibers and migration of granule neurons in the cerebellumDevelopmental Biology, 2009
- N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastomaGenes & Development, 2009
- Two Tumor Suppressors, p27Kip1 and Patched-1, Collaborate to Prevent MedulloblastomaMolecular Cancer Research, 2009
- The HECT Family of E3 Ubiquitin Ligases: Multiple Players in Cancer DevelopmentCancer Cell, 2008
- The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoproteinNature, 2008
- N-Mycand the cyclin-dependent kinase inhibitors p18Ink4cand p27Kip1coordinately regulate cerebellar developmentProceedings of the National Academy of Sciences, 2006
- Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2Cell Death & Differentiation, 2003
- Development of mice expressing a single D-type cyclinGenes & Development, 2002
- Brain lipid-binding protein (BLBP): A novel signaling system in the developing mammalian CNSNeuron, 1994