TY - JOUR
T1 - The adaptor protein CD2AP is a coordinator of neurotrophin signaling-mediated axon arbor plasticity
AU - Harrison, Benjamin J.
AU - Venkat, Gayathri
AU - Lamb, James L.
AU - Hutson, Tom H.
AU - Drury, Cassa
AU - Rau, Kristofer K.
AU - Bunge, Mary Barlett
AU - Mendell, Lorne M.
AU - Gage, Fred H.
AU - Johnson, Richard D.
AU - Hill, Caitlin E.
AU - Rouchka, Eric C.
AU - Moon, Lawrence D.F.
AU - Petruska, Jeffrey C.
N1 - Funding Information:
This work was supported by the CDRF International Consortium on Spinal Cord Injury Research to M.B.B., L.M.M., and F.H.G., Kentucky Spinal Cord and Head Injury Research Trust Grant 09-12A to J.C.P., Paralyzed Veterans of America Fellowship to B.J.H., National Institutes of Health Grants P20RR016481 to E.C.R., 3P20RR016481-09S1 and P20GM103436 to E.C.R. and B.J.H., P30GM103507 to supporting Core staff and facilities of the Kentucky Spinal Cord Injury Research Center, and R21NS080091, R21NS071299, and R01NS094741 to J.C.P. The article contents are solely the responsibility of the authors and do not represent the official views
Publisher Copyright:
© 2016 the authors.
PY - 2016/4/13
Y1 - 2016/4/13
N2 - Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth. In non-neuronal cells, CD2AP, like other adaptor proteins, functions to selectively control the spatial/temporal assembly of multiprotein complexes that transmit intracellular signals. AlthoughCD2APpolymorphisms are associated with increased risk of late-onset Alzheimer’s disease, its role in axon growth is unknown. Assessments of neurite arbor structure in vitro revealedCD2APoverexpression, and siRNA-mediated knockdown, modulated (1) neurite length, (2) neurite complexity, and (3) growth cone filopodia number, in accordance with CD2AP expression levels.Weshow, for the first time, that CD2AP forms a novel multiprotein complex with the NGF receptor TrkA and the PI3K regulatory subunit p85, with the degree of TrkA:p85 association positively regulated by CD2AP levels. CD2AP also regulates NGF signaling through AKT, but not ERK, and regulates long-range signaling though TrkA+/RAB5+ signaling endosomes. CD2APmRNAand protein levels were increased in neurons during collateral sprouting but decreased following injury, suggesting that, although typically considered together, these two adult axonal growth processes are fundamentally different. These data position CD2AP as a major intracellular signaling molecule coordinating NGF signaling to regulate collateral sprouting and structural plasticity of intact adult axons.
AB - Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth. In non-neuronal cells, CD2AP, like other adaptor proteins, functions to selectively control the spatial/temporal assembly of multiprotein complexes that transmit intracellular signals. AlthoughCD2APpolymorphisms are associated with increased risk of late-onset Alzheimer’s disease, its role in axon growth is unknown. Assessments of neurite arbor structure in vitro revealedCD2APoverexpression, and siRNA-mediated knockdown, modulated (1) neurite length, (2) neurite complexity, and (3) growth cone filopodia number, in accordance with CD2AP expression levels.Weshow, for the first time, that CD2AP forms a novel multiprotein complex with the NGF receptor TrkA and the PI3K regulatory subunit p85, with the degree of TrkA:p85 association positively regulated by CD2AP levels. CD2AP also regulates NGF signaling through AKT, but not ERK, and regulates long-range signaling though TrkA+/RAB5+ signaling endosomes. CD2APmRNAand protein levels were increased in neurons during collateral sprouting but decreased following injury, suggesting that, although typically considered together, these two adult axonal growth processes are fundamentally different. These data position CD2AP as a major intracellular signaling molecule coordinating NGF signaling to regulate collateral sprouting and structural plasticity of intact adult axons.
KW - Collateral sprouting
KW - Nerve growth factor
KW - Neural plasticity
KW - Signalosome
KW - Spared dermatome
KW - Transcriptomics
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U2 - 10.1523/JNEUROSCI.2423-15.2016
DO - 10.1523/JNEUROSCI.2423-15.2016
M3 - Article
C2 - 27076424
AN - SCOPUS:84963751767
VL - 36
SP - 4259
EP - 4275
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 15
ER -