A SnoN-Ccd1 Pathway Promotes Axonal Morphogenesis in the Mammalian Brain

• Published in: The Journal of neuroscience Vol. 29; no. 13; pp. 4312 - 4321
• Main Authors: Ikeuchi, Yoshiho, Stegmuller, Judith, Netherton, Stuart, Huynh, Mai Anh, Masu, Masayuki, Frank, David, Bonni, Shirin, Bonni, Azad
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01-04-2009; Society for Neuroscience
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Axons - physiology; Cells, Cultured; Cerebellum - cytology; Chlorocebus aethiops; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; Gene Expression Regulation - genetics; Green Fluorescent Proteins - genetics; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MAP Kinase Kinase 4 - metabolism; MAP Kinase Kinase Kinases - metabolism; Microarray Analysis - methods; Mitogen-Activated Protein Kinase Kinase Kinase 11; Morphogenesis - genetics; Morphogenesis - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - cytology; Rats; Rats, Long-Evans; RNA Interference - physiology; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection - methods
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0126-09.2009

The transcriptional corepressor SnoN is a critical regulator of axonal morphogenesis, but how SnoN drives axonal growth is unknown. Here, we report that gene-profiling analyses in cerebellar granule neurons reveal that the large majority of genes altered upon SnoN knockdown are surprisingly downregulated, suggesting that SnoN may activate transcription in neurons. Accordingly, we find that the transcriptional coactivator p300 interacts with SnoN, and p300 plays a critical role in SnoN-induced axon growth. We also identify the gene encoding the signaling scaffold protein Ccd1 as a critical target of SnoN in neurons. Ccd1 localizes to the actin cytoskeleton, is enriched at axon terminals in neurons, and activates the axon growth-promoting kinase JNK (c-Jun N-terminal protein kinase). Knockdown of Ccd1 in neurons reduces axonal length and suppresses the ability of SnoN to promote axonal growth. Importantly, Ccd1 knockdown in rat pups profoundly impairs the formation of granule neuron parallel fiber axons in the rat cerebellar cortex in vivo. These findings define a novel SnoN-Ccd1 link that promotes axonal growth in the mammalian brain, with important implications for axonal development and regeneration.