Regulate Axon Branching by the Cyclic GMP Pathway via Inhibition of Glycogen Synthase Kinase 3 in Dorsal Root Ganglion Sensory Neurons

Zhao, Zhen; Wang, Zheng; Gu, Ying; Feil, Robert; Hofmann, Franz; Ma, Le

doi:10.1523/jneurosci.3770-08.2009

Cited by 72 publications

(95 citation statements)

References 49 publications

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“…5E,F). These results suggest that, in addition to Rac1 activation, Dock3-dependent GSK-3␤ phosphorylation (i.e., inactivation) plays a role in the BDNF-mediated axonal outgrowth and cell polarity (Kim et al, 2006;Zhao et al, 2009).…”

Section: Dock3 Induces Phosphorylation Of Gsk-3␤ At the Plasma Membranementioning

confidence: 92%

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Namekata

Harada²,

Guo³

et al. 2012

J. Neurosci.

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Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolinhomologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3␤ (GSK-3␤) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3␤ and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3␤ was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly.

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Section: Dock3 Induces Phosphorylation Of Gsk-3␤ At the Plasma Membranementioning

confidence: 92%

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Namekata

Harada²,

Guo³

et al. 2012

J. Neurosci.

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“…More general inhibition of GSK-3 may induce multiple foci along the axon capable of supporting efficient tubulin polymerization, thus resulting in branching. In DRG neurons, cGMP is an important mediator of axon branching, and a key cGMP dependent protein kinase (PrkG1) directly binds to and regulates GSK-3 activity (Zhao et al 2009). There is a clear in vivo correlate to these observations, because elimination of PrkG1 strongly reduces the normal bifurcation of the central process of DRG neurons.…”

Section: Gsk-3 and Axon Elongationmentioning

confidence: 99%

Initiating and Growing an Axon

Polleux¹,

Snider²

2010

Cold Spring Harbor Perspectives in Biology

161

127

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The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system. Dendrites and axons are molecularly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon, which makes presynaptic contacts onto target cells. This article reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to initiate and extend a single axon during development. Remarkably, neurons can polarize to form a single axon, multiple dendrites, and later establish functional synaptic contacts in reductionist in vitro conditions. This approach became, and remains, the dominant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro (Dotti et al. 1988). At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro, axon initiation and elongation are largely intrinsic properties of neurons that are established in the absence of relevant extracellular cues. However, the importance of extracellular cues to axon initiation and outgrowth in vivo is emerging as a major theme in neural development (Barnes and Polleux 2009). In this article, we focus our attention on the extracellular cues and signaling pathways required in vivo for axon initiation and axon extension.

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“…A cGMP signaling cascade composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2 (also known as GC-B or Npr-B), and the cGMPdependent kinase I␣ (cGKI␣, also termed PKGI␣) regulates the first-order bifurcation of DRG axons in the dorsal column. In the absence of any of these components, sensory axons no longer bifurcate and instead form solitary stem axons that turn in either the rostral or caudal direction (Schmidt et al, 2002(Schmidt et al, , 2007(Schmidt et al, , 2009Zhao and Ma, 2009;Zhao et al, 2009). Factors implicated in collateral formation of DRG axons are currently unknown, while terminal branching is regulated by SAD (synapses of amphids defective) kinases (Lilley et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Bifurcation of Axons from Cranial Sensory Neurons Is Disabled in the Absence of Npr2-Induced cGMP Signaling

2014

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Axonal branching is a prerequisite for the establishment of complex neuronal circuits and their capacity for parallel information processing. Previously, we have identified a cGMP signaling pathway composed of the ligand C-type natriuretic peptide (CNP), its receptor, the guanylyl cyclase natriuretic peptide receptor 2 (Npr2), and the cGMP-dependent kinase I␣ (cGKI␣) that regulates axon bifurcation of dorsal root ganglion (DRG) neurons in the spinal cord. Now we asked whether this cascade also controls axon bifurcation elsewhere in the nervous system. An Npr2-lacZ reporter mouse line was generated to clarify the pattern of the CNP receptor expression. It was found that during the period of axonal outgrowth, Npr2 and cGKI␣ were strongly labeled in neurons of all cranial sensory ganglia (gV, gVII, gVIII, gIX, and gX). In addition, strong complementary expression of CNP was detected in the hindbrain at the entry zones of sensory afferents. To analyze axon branching in individual Npr2-positive neurons, we generated a mouse mutant expressing a tamoxifen-inducible variant of Cre recombinase expressed under control of the Npr2-promoter (Npr2-CreER T2 ). After crossing this strain with conditional reporter mouse lines, we revealed that the complete absence of Npr2 activity indeed prohibited the bifurcation of cranial sensory axons in their entrance region. Consequently, axons only turned in either an ascending or descending direction, while collateral formation and growth of the peripheral arm was not affected. These findings indicate that in neurons of the cranial sensory ganglia, as in DRG neurons, cGMP signals are necessary for the execution of an axonal bifurcation program.

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Regulate Axon Branching by the Cyclic GMP Pathway via Inhibition of Glycogen Synthase Kinase 3 in Dorsal Root Ganglion Sensory Neurons

Cited by 72 publications

References 49 publications

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Initiating and Growing an Axon

Bifurcation of Axons from Cranial Sensory Neurons Is Disabled in the Absence of Npr2-Induced cGMP Signaling

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