Emerging roles of Wnts in the adult nervous system

Inestrosa, Nibaldo C.; Arenas, Ernest

doi:10.1038/nrn2755

Cited by 558 publications

(503 citation statements)

References 128 publications

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“…For example, LRRK2 has been associated with Wnt signalling pathways 76, which are essential for the acute regulation of synaptic function; a function that is dysregulated in the premotor symptom stages of rodent models of PD 180. From this prospective, the involvement of LRRK2 in Wnt signalling is an exciting possibility that may give a reason for the alteration in gene expression, as well as disruption of vesicle trafficking 181, which are implicated in PD. Another interesting connection is between LRRK2 and the autophagy/lysosomal/Golgi network, because alteration of the proteolytic balance within the cell may be the reason for the build‐up of toxic aggregates of amyloidogenic α‐synuclein, as implicated in PD.…”

Section: Discussionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Section: Discussionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…Although a role for Wnts in the formation of both central and peripheral synapses is well established (37,38), a crucial unanswered question is whether certain Wnt isoforms promote the assembly of specific types of synapses, thereby affecting the ratio of excitatory/inhibitory inputs. In sharp contrast to other Wnts, like Wnt5a (23,25), Wnt7a specifically promotes the formation and function of excitatory synapses, whereas inhibitory synapses are unaffected.…”

Section: Discussionmentioning

confidence: 99%

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca ²⁺ /Calmodulin-dependent protein kinase II

Ciani¹,

Boyle²,

Dickins³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

195

248

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The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca 2+ /Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.Wnt7a | Dvl1 mutant | plasticity T he formation of functional neuronal circuits requires the assembly of different types of synapses with great specificity. The development of an appropriate balance of glutamatergic excitatory and GABAergic inhibitory synapses (E/I ratio) is essential for proper circuit function (1, 2) because an imbalance in the E/I ratio can result in neurological disorders (3-5). Some synaptogenic factors regulate both excitatory and inhibitory synapses (6, 7), whereas other synaptic organizers are more specific (8-10). However, the precise mechanisms by which synaptic organizing signals regulate excitatory and inhibitory synapses remain poorly understood.In the central nervous system, most excitatory inputs are located on dendritic spines, postsynaptic protrusions that function as domains where synaptic activity is regulated in a compartmentalized manner (11-13). Several intracellular molecules have been implicated in the formation and maturation of dendritic spines (14-16), but the mechanisms by which extracellular factors signal through intracellular regulators to promote spine development and maturation remain poorly characterized.Wnt secreted proteins are synaptic organizers that stimulate the formation of central and peripheral synapses (17-19) by promoting presynaptic assembly (20) and the clustering of postsynaptic components (19,(21)(22)(23)(24). In cultured neurons, Wnt5a regulates postsynaptic development of both GABAergic and glutamatergic synapses (24,25). However, it is unclear whether other Wnts play a...

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“…The sustained expression of Wnt ligands and Wnt signaling components in the mature mammalian CNS and their involvement in neuropathologies suggest that these signaling cascades might also play a part in synaptic maintenance and function beyond embryonic development (10,11). However, because of the pleiotropy and complexity of Wnt signaling, it has been difficult to dissect the components of Wnt signaling present in mature neurons and their role, if any, in the regulation of established synaptic connections and synaptic transmission.…”

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confidence: 99%

RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

Cerpa¹,

Latorre-Esteves

Barría³

2015

Proc. Natl. Acad. Sci. U.S.A.

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Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDARmediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development.NMDA receptors | Wnt signaling | synaptic transmission | RoR2 | glutamate receptors

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Emerging roles of Wnts in the adult nervous system

Cited by 558 publications

References 128 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca ²⁺ /Calmodulin-dependent protein kinase II

RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

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Emerging roles of Wnts in the adult nervous system

Cited by 558 publications

References 128 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca 2+ /Calmodulin-dependent protein kinase II

RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

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Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca ²⁺ /Calmodulin-dependent protein kinase II