Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4259-4275 |
| Number of pages | 17 |
| Journal | Journal of Neuroscience |
| Volume | 36 |
| Issue number | 15 |
| DOIs | |
| State | Published - Apr 13 2016 |
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Keywords
- Collateral sprouting
- Nerve growth factor
- Neural plasticity
- Signalosome
- Spared dermatome
- Transcriptomics
ASJC Scopus subject areas
- Neuroscience(all)
- Medicine(all)
Cite this
The adaptor protein CD2AP is a coordinator of neurotrophin signaling-mediated axon arbor plasticity. / Harrison, Benjamin J.; Venkat, Gayathri; Lamb, James L.; Hutson, Tom H.; Drury, Cassa; Rau, Kristofer K.; Bunge, Mary B; Mendell, Lorne M.; Gage, Fred H.; Johnson, Richard D.; Hill, Caitlin E.; Rouchka, Eric C.; Moon, Lawrence D F; Petruska, Jeffrey C.
In: Journal of Neuroscience, Vol. 36, No. 15, 13.04.2016, p. 4259-4275.Research output: Contribution to journal › Article
}
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 B
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.
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
UR - http://www.scopus.com/inward/record.url?scp=84963751767&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963751767&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2423-15.2016
DO - 10.1523/JNEUROSCI.2423-15.2016
M3 - Article
VL - 36
SP - 4259
EP - 4275
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 15
ER -