Jandke, A.; (2008) The role of the c-Jun ubiquitin ligase Fbw7 in the nervous system. Doctoral thesis , University of London.

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Abstract

Fbw7 belongs to the family of F-box proteins, which function as substrate recognition subunits of SCF complexes. Fbw7 controls the stability of several proteins including cyclin E, the Notch intracellular domain and c-Myc. In 2004 our lab additionally identified phospho-c-Jun as an Fbw7 substrate, c-Jun is part of the AP-1 transcription complex, whose activity is strongly induced in response to numerous signals such as growth factors, cytokines and extracellular stresses. Furthermore elevated phospho-c-Jun levels induce neuronal apoptosis. To investigate the significance of c-Jun regulation by Fbw7 in the nervous system, I generated mice harbouring a floxed fbw7 allele, fbw7. fbw7 mice were bred to various Cre transgenic lines that express the Cre recombinase under nervous system specific promoters to obtain mice with a tissue specific deletion of Fbw7. I confirmed published results that ubiquitous deletion of Fbw7 mediated by PGK-Cre is lethal. To delete Fbw7 at the stage of neuronal precursors, fbwff mice were crossed to the Nestin-cre line (fbw7). These mice die perinatally and show an increase in apoptosis at El6. As the lethality of the fbw7AN mice does not allow the investigation of Fbw7 in the adult nervous system, further crosses, using other cre-transgenic lines, were set up. Fbw7 deletion in postmitotic neurons (fbw7ApN) causes a Parkinson's disease like phenotype with a severe hindlimb tremor and a reduced cortical cellularity. Fbw7 deletion in the cerebellar vermis (fbw7ACb) resulted in cerebella that are characterised by a reduced size, foliation defects accompanied by an astrocytic gliosis and a phospho-c-Jun dependent Purkinje cell loss. Concomitant deletion of c-Jun in the cerebellum (fbw7ACb :c-junACb) partially rescues the cerebellar phenotype caused by Fbw7 deletion. Thus the data in this thesis demonstrate a role for Fbw7 in cerebellar development and the central nervous system and identify c-Jun as an essential Fbw7 substrate in the nervous system.

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