Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance

Mériane, Mayya; Tcherkezian, Joseph; Webber, Christine A.; Danek, Eric I.; Triki, Ibtissem; McFarlane, Sarah; Bloch‐Gallego, Evelyne; Lamarche-Vane, Nathalie

doi:10.1083/jcb.200405053

Cited by 112 publications

(113 citation statements)

References 42 publications

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“…This is suggested by a similar time course of induction of both DCC and PLC␥ tyrosine phosphorylation and PIP 2 hydrolysis upon netrin-1 stimulation, an attenuation of netrin-1-induced PIP 2 hydrolysis in DCC-Y1420F-expressing cells, and an inhibition of neurite outgrowth by a PLC inhibitor. These observations are consistent with previous studies showing that DCC tyrosine phosphorylation contributes to netrin-1-induced neurite outgrowth (41), that PLC␥ signaling is required in nerve growth factor-and netrin-1-induced growth cone guidance of Xenopus spinal neurons (27), and that IP 3 receptor-mediated calcium release from intracellular stores plays an important role in axonal extension of chick dorsal root ganglia (42).…”

Section: Discussionsupporting

confidence: 82%

“…In aggregate, our results suggest that neither P3 domain-mediated dimerization nor P3-FAK binding appeared to be required for netrin-1 induction of PLC signaling, thus implicating an involvement of other P3-dependent-binding proteins in this event. DCC has been found to be phosphorylated at tyrosine 1420 (Tyr 1420 ), a site close to the P3 region and implicated in netrin-1 signaling (19,41). We thus examined whether DCC-Tyr 1420 phosphorylation contributes to netrin-1-induced PIP 2 hydrolysis.…”

Section: Independence Of Dcc-p3 Homodimerization or Fak For Netrin-1-mentioning

confidence: 99%

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DCC-dependent Phospholipase C Signaling in Netrin-1-induced Neurite Elongation

Xie

Hong

Xiao

et al. 2006

Journal of Biological Chemistry

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Netrins, a family of secreted molecules, play important roles in axon pathfinding during nervous system development. Although phosphatidylinositol signaling has been implicated in this event, how netrin-1 regulates phosphatidylinositol signaling remains poorly understood. Here we provide evidence that netrin-1 stimulates phosphatidylinositol bisphosphate hydrolysis in cortical neurons. This event appears to be mediated by DCC (deleted in colorectal cancer), but not neogenin or Unc5h2. Netrin-1 induces phospholipase C␥ (PLC␥) tyrosine phosphorylation. Inhibition of PLC activity attenuates netrin-1-induced cortical neurite outgrowth. These results suggest that netrin-1 regulates phosphatidylinositol turnover and demonstrate a crucial role of PLC signaling in netrin-1-induced neurite elongation.Proper wiring in developing brains requires neurite outgrowth and growth cone navigation. Netrins, a family of secreted factors, promote axon outgrowth (1-4). In addition, netrins are able to guide neuronal growth cones and regulate neuronal branching in the developing nervous system (1-4). Netrins act through two classes of receptors: DCC and Unc5. The DCC family includes DCC and neogenin in vertebrates (5), Unc40 in Caenorhabditis elegans (6), and Frazzled in Drosophila (7,8). DCC is required for the attractive response (9). Unc5 in C. elegans and Unc5A, -5B, and -5C in vertebrates belong to the Unc5 family, which appears to mediate the repulsive response (10 -14).DCC and Unc5 proteins are transmembrane proteins without any obvious catalytic activity, and thus it remains unknown exactly how they initiate downstream signaling to mediate or regulate axonal outgrowth and guidance. Nevertheless, perturbation of Rho family GTPases inhibits netrin-induced neurite outgrowth (15). Pharmacological inhibition of extracellular signal-regulated kinase (ERK) attenuates netrin-1-induced neurite outgrowth and growth cone turning (16,17). Inhibition of focal adhesion kinase (FAK), 3 a major tyrosine kinase localized in focal adhesions and implicated in cell spreading and migration, blocks netrin-1-induced neurite elongation and growth cone guidance (18 -20). Treatment of wortmannin, an inhibitor of phosphatidylinositol 3-kinase, attenuates netrin-1-induced growth cone turning in Xenopus spinal neurons (27).Phosphoinositides are quantitatively minor phospholipids of cell membranes, but their metabolism is highly active and tightly regulated. They (e.g. PIP 2 ) function either as precursors of second messengers such as inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol or by directly interacting with both actin-binding and pleckstrin homology domaincontaining proteins to regulate their spatiotemporal distribution and/or activity. In addition, PIP 2 functions as a cofactor for small GTP-binding proteins (e.g. Arf) and phospholipase D (21, 22). In the nervous system, PIP 2 plays an important role in membrane trafficking at the synapse. Synaptic vesicle exocytosis and endocytosis require phosphatidylinositol 4,5-bisphosphate (23-26). Usin...

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Section: Discussionsupporting

confidence: 82%

Section: Independence Of Dcc-p3 Homodimerization or Fak For Netrin-1-mentioning

confidence: 99%

DCC-dependent Phospholipase C Signaling in Netrin-1-induced Neurite Elongation

Xie

Hong

Xiao

et al. 2006

Journal of Biological Chemistry

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“…However, the finding that the enhancement of neurite outgrowth induced by ␤-cyclodextrin treatment is accompanied by the recruitment of Fyn to lipid rafts and that the Src family inhibitor PP2 inhibits axonal elongation induced by ␤-cyclodextrin treatment suggests that an increased level of raft-localized Fyn is in part involved in ␤-cyclodextrin-induced axonal elongation in hippocampal neurons. This notion is supported by previous studies showing that Src family kinases, including Fyn, play a critical role in axon outgrowth (27,28) and that lipid raft-localized Fyn is more catabolically active than non-raft-localized Fyn (29,30).…”

Section: Discussionsupporting

confidence: 76%

Cholesterol-mediated Neurite Outgrowth Is Differently Regulated between Cortical and Hippocampal Neurons

Zou

Minagawa

et al. 2005

Journal of Biological Chemistry

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The acquisition of neuronal type-specific morphogenesis is a central feature of neuronal differentiation and has important consequences for region-specific nervous system functions. Here, we report that the cell type-specific cholesterol profile determines the differential modulation of axon and dendrite outgrowths in hippocampal and cerebral cortical neurons in culture. The extent of axon and dendrite outgrowths is greater and the polarity formation occurs earlier in cortical neurons than in hippocampal neurons. The cholesterol concentrations in total homogenate and the lipid rafts from hippocampal neurons are significantly higher than those from cortical neurons. Cholesterol depletion by ␤-cyclodextrin markedly enhanced the neurite outgrowth and accelerated the establishment of neuronal polarity in hippocampal neurons, which were similarly observed in nontreated cortical neurons, whereas cholesterol loading had no effects. In contrast, both depletion and loading of cholesterol decreased the neurite outgrowths in cortical neurons. The stimulation of neurite outgrowth and polarity formation induced by cholesterol depletion was accompanied by an enhanced localization of Fyn, a Src kinase, in the lipid rafts of hippocampal neurons. A concomitant treatment with ␤-cyclodextrin and a Src family kinase inhibitor, PP2, specifically blocked axon outgrowth but not dendrite outgrowth (both of which were enhanced by ␤-cyclodextrin) in hippocampal neurons, suggesting that axon outgrowth modulated by cholesterol is induced in a Fyn-dependent manner. These results suggest that cellular cholesterol modulates axon and dendrite outgrowths and neuronal polarization under culture conditions and also that the difference in cholesterol profile between hippocampal and cortical neurons underlies the difference in neurite outgrowth between these two types of neurons.Neurons contain two types of processes, axons and dendrites, which are structurally and functionally distinct and play different roles in the maintenance of brain functions. There are studies showing the significant role of lipids in the formation of neuronal polarity; it has been shown that phospholipids regulate neurite outgrowth in cultured neurons (1) and that the correct distribution of axonal membrane proteins requires the formation of sphingomyelin/cholesterol-rich microdomains, lipid rafts, and the maturation of the axonal plasma membrane requires the up-regulation of sphingomyelin synthesis (2, 3). Cholesterol also plays a prominent role in raft-mediated trafficking and sorting, because cholesterol depletion by methyl-␤-cyclodextrin impedes trafficking from the trans-Golgi network to the apical membrane (4). It has been shown that cholesterol modulates dendrite outgrowth (5), that its deficiency enhances phosphorylation of tau and axonal depolymerization (6), and that axonal regeneration is dependent on local cholesterol reutilization in vivo (7). In addition, cholesterol supplied as glial lipoproteins stimulates the axon outgrowth of central nervous system neurons...

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“…It has been shown that netrin-1 induces tyrosine phosphorylation of DCC in commissural neurons and that this phosphorylation is crucial for netrin-1-dependent axon outgrowth function (Meriane et al, 2004). To analyze DCC phosphorylation, HEK293T cells transfected with myc-tagged DCC were treated with netrin-1.…”

Section: Effect Of the Abrogation Of Hs Expression On Netrin-1 Downstmentioning

confidence: 99%

Netrin-1/DCC Signaling in Commissural Axon Guidance Requires Cell-Autonomous Expression of Heparan Sulfate

Matsumoto¹,

Irie²,

Inatani³

et al. 2007

J. Neurosci.

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There is increasing evidence that heparan sulfate (HS) plays an essential role in various axon guidance processes. These observations, however, have not addressed whether HS is required cell autonomously as an axonal coreceptor or as an environmental factor that modulates the localization of guidance molecules in the terrain in which growing axons navigate. Here we demonstrate that netrin-1-mediated commissural axon guidance requires cell-autonomous expression of HS in commissural neurons in vivo. We used the Wnt1 -Cre transgene to drive region-specific ablation of Ext1, which encodes an enzyme essential for HS synthesis, in the dorsal part of the spinal cord. Remarkably, Wnt1-Cre-mediated ablation of Ext1 causes commissural axon pathfinding defects that share similarities with those of Netrin-1-deficient and DCC (deleted in colorectal cancer)-deficient mice. Neither Ext1-deficient dorsal spinal cord explants nor wild-type explants in which HS expression was ablated could extend axons in response to netrin-1. Intracellular signaling downstream of netrin-1 and DCC was defective in Ext1-deficient commissural neurons and in DCC-transfected HEK293T cells from which HS was removed. These results demonstrate that the expression of HS by commissural neurons is essential for these neurons to transduce netrin-1 signals, thus providing evidence for a cell-autonomous role of HS in netrin-1/DCC-mediated axon guidance.

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Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance

Cited by 112 publications

References 42 publications

DCC-dependent Phospholipase C Signaling in Netrin-1-induced Neurite Elongation

DCC-dependent Phospholipase C Signaling in Netrin-1-induced Neurite Elongation

Cholesterol-mediated Neurite Outgrowth Is Differently Regulated between Cortical and Hippocampal Neurons

Netrin-1/DCC Signaling in Commissural Axon Guidance Requires Cell-Autonomous Expression of Heparan Sulfate

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