Abstract
Axonal growth is fundamental to the establishment of neuronal connectivity in the brain. However, the cell-intrinsic mechanisms that govern axonal morphogenesis remain to be elucidated. The ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC) suppresses the growth of axons in postmitotic neurons. Here, we report that Cdh1-APC operates in the nucleus to inhibit axonal growth. We also identify the transcriptional corepressor SnoN as a key target of neuronal Cdh1-APC that promotes axonal growth. Cdh1 forms a physical complex with SnoN and stimulates the ubiquitin-dependent proteasomal degradation of SnoN in neurons. Knockdown of SnoN in neurons significantly reduces axonal growth and suppresses Cdh1 RNAi enhancement of axonal growth. In addition, SnoN knockdown in vivo suggests an essential function for SnoN in the development of granule neuron parallel fibers in the cerebellar cortex. These findings define Cdh1-APC and SnoN as components of a cell-intrinsic pathway that orchestrates axonal morphogenesis in a transcription-dependent manner in the mammalian brain.
MeSH terms
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Anaphase-Promoting Complex-Cyclosome
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Animals
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Animals, Genetically Modified
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Animals, Newborn
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Brain / cytology
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Brain / growth & development*
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Brain / metabolism*
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Cell Differentiation / physiology*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cerebellar Cortex / cytology
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Cerebellar Cortex / growth & development
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Cerebellar Cortex / metabolism
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Down-Regulation / physiology
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Growth Inhibitors / genetics
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Growth Inhibitors / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Macromolecular Substances / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Organ Culture Techniques
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Interference / physiology
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Rats
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Rats, Long-Evans
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Ubiquitin-Protein Ligase Complexes / genetics
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Ubiquitin-Protein Ligase Complexes / metabolism*
Substances
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Growth Inhibitors
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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SKIL protein, human
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Skil_v1 protein, rat
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Transcription Factors
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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Proteasome Endopeptidase Complex