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The Journal of Neuroscience, August 29, 2007, 27(35):9503-9512; doi:10.1523/JNEUROSCI.1408-07.2007

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Cellular/Molecular
Neuronal Morphogenesis Is Regulated by the Interplay between Cyclin-Dependent Kinase 5 and the Ubiquitin Ligase Mind Bomb 1

Eun-Ah Choe,¹ Lujian Liao,¹ Jian-Ying Zhou,¹ Dongmei Cheng,¹ Duc M. Duong,¹ Peng Jin,¹ Li-Huei Tsai,² and Junmin Peng¹

¹Department of Human Genetics, Center for Neurodegenerative Diseases, School of Medicine, Emory University, Atlanta, Georgia 30322, and ²The Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Correspondence should be addressed to Junmin Peng at the above address. Email: jpeng{at}genetics.emory.edu

Neuronal communication requires the coordinated assembly of polarized structures including axons, dendrites, and synapses. Here, we report the identification of a ubiquitin ligase mind bomb 1 (Mib1) in the postsynaptic density and the characterization of its role in neuronal morphogenesis. Expression of Mib1 inhibits neurite outgrowth in cell culture and its gene deletion enhances synaptic growth at the neuromuscular junction in Drosophila. The analysis of Mib1 interactome by mass spectrometry revealed that Mib1 primarily interacts with membrane trafficking proteins [e.g., EEA1 (early endosomal antigen 1), Rab11-interacting proteins, and SNAP25 (synaptosomal-associated protein of 25 kDa)-like protein] and cell adhesion components (e.g., catenin, coronin, dystrobrevin, and syndecan), consistent with its previously reported function in protein sorting. More interestingly, Mib1 is associated with deubiquitinating enzymes, BRCC36 and the mammalian ortholog of fat facets, and a number of kinases, such as casein kinase II, MARK (microtubule affinity regulating kinase)/PAR1, and cyclin-dependent kinase 5 (CDK5). Further characterization of the Mib1-CDK5 interaction indicated that the N-terminal domain of Mib1 directly binds to the regulatory subunit p35 of the CDK5 complex. In cell culture, Mib1 induces the relocalization of p35/CDK5 without affecting its degradation. Surprisingly, p35/CDK5 downregulates the protein level of Mib1 by its kinase activity, and completely rescues the Mib1-induced inhibitory effect on neurite morphology. p35/CDK5 also genetically interacts with Mib1 in the fly according to the rough-eye phenotype. The data strongly support that the negative interplay between Mib1 and p35/CDK5 may integrate the activities of multiple pathways during neuronal development.

Key words: neuronal morphogenesis; proteomics; ubiquitin; CDK5; mind bomb; mass spectrometry

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Received Dec. 2, 2006; revised July 14, 2007; accepted July 17, 2007.

Correspondence should be addressed to Junmin Peng at the above address. Email: jpeng{at}genetics.emory.edu

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