Functional analysis of the CNS-specific F-box protein FBXO41 in cerebellar development
Functional analysis of the CNS-specific F-box protein FBXO41 in cerebellar development
von Chaitali Mukherjee
Datum der mündl. Prüfung:2015-06-08
Erschienen:2015-10-16
Betreuer:Dr. Judith Stegmüller
Gutachter:Dr. Judith Stegmüller
Gutachter:Prof. Dr. Mikael Simons
Dateien
Name:Chaitali_Mukherjee PhD thesis 2015.pdf
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Format:PDF
Zusammenfassung
Englisch
Neurodevelopment is a highly dynamic process governed by the tight orchestration of events such as neurogenesis, neuronal migration, morphogenesis and synaptogenesis that ultimately shape the brain. These neurodevelopmental events are tightly regulated by the interplay of cell-extrinsic and intrinsic mechanisms. Over the past decades, the ubiquitin proteasome system has emerged as an intrinsic regulator of neurodevelopment as well as disease. In this study, I explored the function of the CNS-specific F-box protein FBXO41 in vivo and established it as a key regulator of cerebellar development. I found that loss of FBXO41 results in a severely ataxic and uncoordinated gait in mice, along with impaired granule neuron migration, neurodegeneration and axon growth defects in the cerebellum. In addition, I identified FBXO41 as the second F-box protein to form an SCF-like E3 ligase complex with cullin7. Furthermore, I discovered that FBXO41-Cul7 non-proteolytically ubiquitinates the cytoskeletal protein neurofilament medium polypeptide (NFM), thereby stabilizing it. Last but not the least, I uncovered that FBXO41-Cul7 operates upstream of NFM in the pathway of axon growth regulation. Collectively, my study has uncovered the function of FBXO41 in cerebellar development and has identified FBXO41-Cul7 as a novel E3 ligase providing the first insights into its ligase activity and axon growth regulation.
Keywords: Ataxia; Axon growth; Cerebellum; Cullin7; neuronal migration; neurofilament; FBXO41