Cell-Intrinsic Regulation of Axonal Morphogenesis by the Cdh1-APC Target SnoN

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.

[1]  D. Elliott,et al.  Independent Regulation of Synaptic Size and Activity by the Anaphase-Promoting Complex , 2004, Cell.

[2]  J Wade Harper,et al.  The anaphase-promoting complex: it's not just for mitosis any more. , 2002, Genes & development.

[3]  Y. Jan,et al.  Rho family GTP-binding proteins in growth cone signalling. , 1997, Current opinion in neurobiology.

[4]  S. Higashijima,et al.  Functional Repression of Islet-2 by Disruption of Complex with Ldb Impairs Peripheral Axonal Outgrowth in Embryonic Zebrafish , 2001, Neuron.

[5]  S. Mcconnell,et al.  Faculty Opinions recommendation of Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. , 2005 .

[6]  J. Isola,et al.  Ski-related novel protein N (SnoN), a negative controller of transforming growth factor-beta signaling, is a prognostic marker in estrogen receptor-positive breast carcinomas. , 2003, Cancer research.

[7]  Jiri Bartek,et al.  Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex , 1999, Nature.

[8]  Sarah B Tegen,et al.  The Transforming Activity of Ski and SnoN Is Dependent on Their Ability to Repress the Activity of Smad Proteins* , 2003, Journal of Biological Chemistry.

[9]  Qiang Zhou,et al.  The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. , 1999, Genes & development.

[10]  S. Ishii,et al.  Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. , 1999, Genes & development.

[11]  A. Bonni,et al.  Moving past proliferation: new roles for Cdh1–APC in postmitotic neurons , 2005, Trends in Neurosciences.

[12]  P. Hieter,et al.  The anaphase-promoting complex: new subunits and regulators. , 1999, Annual review of biochemistry.

[13]  Jeffrey L Goldberg,et al.  Intrinsic neuronal regulation of axon and dendrite growth , 2004, Current Opinion in Neurobiology.

[14]  S. Hughes,et al.  Activation of the c-ski oncogene by overexpression , 1991, Journal of virology.

[15]  R. Weinberg,et al.  Interaction of the Ski Oncoprotein with Smad3 Regulates TGF-β Signaling , 1999 .

[16]  C. Holt,et al.  Chemotropic Responses of Retinal Growth Cones Mediated by Rapid Local Protein Synthesis and Degradation , 2001, Neuron.

[17]  E. Medrano,et al.  Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling. , 2001, Cancer research.

[18]  Sylvia M. Wilson,et al.  SnoN Is a Cell Type-specific Mediator of Transforming Growth Factor-β Responses* , 2005, Journal of Biological Chemistry.

[19]  Azad Bonni,et al.  Cdh1-APC Controls Axonal Growth and Patterning in the Mammalian Brain , 2004, Science.

[20]  Artur Kania,et al.  Coordinate Roles for LIM Homeobox Genes in Directing the Dorsoventral Trajectory of Motor Axons in the Vertebrate Limb , 2000, Cell.

[21]  Maria K. Lehtinen,et al.  Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. , 2002, Molecular cell.

[22]  Mu-ming Poo,et al.  Guiding neuronal growth cones using Ca2+ signals. , 2004, Trends in cell biology.

[23]  K. Luo,et al.  Negative Feedback Regulation of TGF-β Signaling by the SnoN Oncoprotein , 1999 .

[24]  J. Kaplan,et al.  The Anaphase-Promoting Complex Regulates the Abundance of GLR-1 Glutamate Receptors in the Ventral Nerve Cord of C. elegans , 2004, Current Biology.

[25]  Paola Arlotta,et al.  Neuronal Subtype-Specific Genes that Control Corticospinal Motor Neuron Development In Vivo , 2005, Neuron.

[26]  J. Chilton.  Molecular mechanisms of axon guidance. , 2006, Developmental biology.

[27]  Sylvia M. Wilson,et al.  SnoN is a cell type-specific mediator of transforming growth factor-beta responses. , 2005, The Journal of biological chemistry.

[28]  Jan-Michael Peters,et al.  The anaphase-promoting complex: proteolysis in mitosis and beyond. , 2002, Molecular cell.

[29]  A. B. Huber,et al.  Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. , 2003, Annual review of neuroscience.

[30]  K. Miyazono,et al.  c-Ski Acts as a Transcriptional Co-repressor in Transforming Growth Factor-β Signaling through Interaction with Smads* , 1999, The Journal of Biological Chemistry.

[31]  R. Weinberg,et al.  SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  E. Dent,et al.  Cytoskeletal Dynamics and Transport in Growth Cone Motility and Axon Guidance , 2003, Neuron.

[33]  Maria K. Lehtinen,et al.  Characterization of a Neurotrophin Signaling Mechanism that Mediates Neuron Survival in a Temporally Specific Pattern , 2003, The Journal of Neuroscience.

[34]  J. Altman.  Development of the Cerebellar System , 1997 .

[35]  Liqun Luo,et al.  Axon Pruning during Drosophila Metamorphosis Evidence for Local Degeneration and Requirement of the Ubiquitin-Proteasome System , 2003, Neuron.

[36]  M. Kirschner,et al.  The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. , 2001, Molecular cell.

[37]  J. Campisi,et al.  Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Kirschner,et al.  Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. , 1996, Molecular biology of the cell.

[39]  M. Kirschner,et al.  The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1. , 2000, Genes & development.

[40]  E. Nagoshi,et al.  Nucleocytoplasmic protein transport and recycling of Ran. , 1999, Cell structure and function.

[41]  S. Mcconnell,et al.  Cortical Neurons Require Otx1 for the Refinement of Exuberant Axonal Projections to Subcortical Targets , 1999, Neuron.

[42]  M. Crair,et al.  Brn3b/Brn3c double knockout mice reveal an unsuspected role for Brn3c in retinal ganglion cell axon outgrowth. , 2002, Development.

[43]  J. Wrana,et al.  Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. , 2001, Genes & development.

[44]  Azad Bonni,et al.  A CaMKII-NeuroD Signaling Pathway Specifies Dendritic Morphogenesis , 2004, Neuron.

[45]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[46]  Y. Jan,et al.  Rho family small GTP-binding proteins in growth cone signalling , 1997, Current Opinion in Neurobiology.