Abstract
Presynaptic axonal differentiation is essential for synapse formation and the establishment of neuronal circuits. However, the mechanisms that coordinate presynaptic development in the brain are largely unknown. We found that the major mitotic E3 ubiquitin ligase Cdc20-anaphase promoting complex (Cdc20-APC) regulates presynaptic differentiation in primary postmitotic mammalian neurons and in the rat cerebellar cortex. Cdc20-APC triggered the degradation of the transcription factor NeuroD2 and thereby promoted presynaptic differentiation. The NeuroD2 target gene encoding Complexin II, which acts locally at presynaptic sites, mediated the ability of NeuroD2 to suppress presynaptic differentiation. Thus, our findings define a Cdc20-APC ubiquitin signaling pathway that governs presynaptic development, which holds important implications for neuronal connectivity and plasticity in the brain.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism
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Anaphase-Promoting Complex-Cyclosome
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Animals
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Axons / metabolism
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Axons / physiology*
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Axons / ultrastructure
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cdc20 Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cerebellar Cortex / cytology
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Cerebellar Cortex / metabolism
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Cerebellar Cortex / ultrastructure
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Gene Knockdown Techniques
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Mutant Proteins / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Presynaptic Terminals / metabolism*
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Rats
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Signal Transduction*
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Synapses / metabolism*
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Synapsins / metabolism
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Synaptic Vesicles / genetics
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Synaptic Vesicles / metabolism
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligase Complexes / genetics
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Ubiquitin-Protein Ligase Complexes / metabolism*
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Adaptor Proteins, Vesicular Transport
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Basic Helix-Loop-Helix Transcription Factors
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Cdc20 Proteins
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Cdc20 protein, rat
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Cell Cycle Proteins
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Mutant Proteins
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Nerve Tissue Proteins
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Neurod2 protein, rat
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Neuropeptides
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Synapsins
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Ubiquitin
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complexin II
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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Ubiquitin-Protein Ligases