Frizzled receptors in neurons: From growth cones to the synapse

Varela-Nallar, Lorena; Ramirez, Valerie; González-Billault, Christian; Inestrosa, Nibaldo C.

doi:10.1002/cm.21022

Cited by 24 publications

(25 citation statements)

References 37 publications

(78 reference statements)

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“…However, because Wnt-5a regulates synaptic development, we first analyzed the synaptic distribution of FZD9 in cultured hippocampal neurons at day in vitro (DIV) 14. Our immunolocalization studies showed that FZD9 was distributed in a punctate pattern in the neuronal processes, as previously reported (31), and co-localized with the postsynaptic density scaffolding protein PSD-95 (Fig. 1A).…”

Section: Postsynaptic Distribution Of the Fzd9 Receptor In Hippocam-supporting

confidence: 88%

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Ramirez

Ramos-Fernández

Henríquez

et al. 2016

Journal of Biological Chemistry

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Wnt ligands play crucial roles in the development and regulation of synapse structure and function. Specifically, Wnt-5a acts as a secreted growth factor that regulates dendritic spine formation in rodent hippocampal neurons, resulting in postsynaptic development that promotes the clustering of the PSD-95 (postsynaptic density protein 95). Here, we focused on the early events occurring after the interaction between Wnt-5a and its Frizzled receptor at the neuronal cell surface. Additionally, we studied the role of heterotrimeric G proteins in Wnt-5a-dependent synaptic development. We report that FZD9 (Frizzled9), a Wnt receptor related to Williams syndrome, is localized in the postsynaptic region, where it interacts with Wnt-5a. Functionally, FZD9 is required for the Wnt-5a-mediated increase in dendritic spine density. FZD9 forms a precoupled complex with G␣ o under basal conditions that dissociates after Wnt-5a stimulation. Accordingly, we found that G protein inhibition abrogates the Wnt-5a-dependent pathway in hippocampal neurons. In particular, the activation of G␣ o appears to be a key factor controlling the Wnt-5a-induced dendritic spine density. In addition, we found that G␤␥ is required for the Wnt-5a-mediated increase in cytosolic calcium levels and spinogenesis. Our findings reveal that FZD9 and heterotrimeric G proteins regulate Wnt-5a signaling and dendritic spines in cultured hippocampal neurons.The Wnt family proteins are secreted growth factors that regulate developmental processes, such as cell fate and polarity and general cell maintenance events, by modulating homeostasis and the cell cycle (1, 2). Furthermore, Wnt signaling controls various steps in the differentiation of the central nervous system (3-5), including axon guidance, dendrite development, synapse formation and plasticity (6, 7). Certain Wnt ligands, such as Wnt-7a and Wnt-3a, regulate the development and activity of the pre-and postsynaptic regions of glutamatergic synapses (8 -10). Similarly, previous results have shown that Wnt-5a regulates the synaptic structure and function by inducing the clustering of PSD-95 through the activation of the c-Jun N-terminal kinase (JNK) (11) and modulates glutamate receptors through nitric oxide production (12). Additionally, Wnt-5a promotes the de novo formation of dendritic spines in hippocampal neurons (13) through the non-canonical Wnt/Ca 2ϩ pathway.The Frizzled (FZD) 2 family has 10 members in vertebrates and represents unconventional G protein-coupled receptors (GPCRs) (14). FZD proteins have been identified as Wnt receptors, and they can mediate the signaling triggered by several Wnt ligands. Wnt-5a activity has been linked to several FZDs receptors and other co-receptors in different model systems (15-18). However, the FZD receptor mediating Wnt-5a signaling and spine formation in hippocampal neurons has not yet been identified.Several signaling cascades can be triggered upon Wnt binding to a FZD receptor, including canonical (i.e. ␤-catenin-dependent) and non-canonical pathways (19). Co...

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Section: Postsynaptic Distribution Of the Fzd9 Receptor In Hippocam-supporting

confidence: 88%

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Ramirez

Ramos-Fernández

Henríquez

et al. 2016

Journal of Biological Chemistry

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“…Although the potential roles of Fz receptors in axonal regeneration after CNS injury have not been studied, it should be noted that, under physiological conditions, these receptors are involved in axonal growth and/or function during CNS development [63]–[67] and adulthood [65], [66]. In agreement with these observations, several Fz receptors are expressed in cultured hippocampal neurons in both their cellular soma and neurites [68]. Interestingly, here we show that in the NL spinal cords, Fz7 is expressed in fine and extremely elongated structures with small engrossments, which may resemble axons.…”

Section: Discussionmentioning

confidence: 54%

Spatio-Temporal Expression Pattern of Frizzled Receptors after Contusive Spinal Cord Injury in Adult Rats

et al. 2012

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BackgroundWnt proteins are a large family of molecules that are critically involved in multiple central nervous system (CNS) developmental processes. Experimental evidences suggest a role for this family of proteins in many CNS disorders, including spinal cord injury (SCI), which is a major neuropathology owing to its high prevalence and chronic sensorimotor functional sequelae. Interestingly, most Wnt proteins and their inhibitors are expressed in the uninjured spinal cord, and their temporal expression patterns are dramatically altered after injury. However, little is known regarding the expression of their better-known receptors, the Frizzled family, after SCI. Thus, the aim of the present study was to evaluate the expression of Frizzled receptors in the damaged spinal cord.FindingsBased on the evidence that Wnts are expressed in the spinal cord and are transcriptionally regulated by SCI in adulthood, we analysed the spatio-temporal mRNA and protein expression patterns of Frizzled receptors after contusive SCI using quantitative RT-PCR and single and double immunohistochemistry, respectively. Our results show that almost all of the 10 known Frizzled receptors were expressed in specific spatial patterns in the uninjured spinal cords. Moreover, the Frizzled mRNAs and proteins were expressed after SCI, although their expression patterns were altered during the temporal progression of SCI. Finally, analysis of cellular Frizzled 5 expression pattern by double immunohistochemistry showed that, in the uninjured spinal cord, this receptor was expressed in neurons, oligodendrocytes, astrocytes, microglia and NG2+ glial precursors. After injury, Frizzled 5 was not only still expressed in oligodendrocytes, astrocytes and NG2+ glial precursors but also in axons at all evaluated time points. Moreover, Frizzled 5 was expressed in reactive microglia/macrophages from 3 to 14 days post-injury.ConclusionsOur data suggest the involvement of Frizzled receptors in physiological spinal cord function and in the cellular and molecular events that characterise its neuropathology.

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“…In addition to central synapses, activity-regulated secretion was also observed at neuromuscular junctions (NMJs) in Drosophila (33). Wnt receptors, especially the Frizzled proteins, are likely located on both the pre- and post-synaptic membrane (11, 34, 35). Thus, the activity-regulated secretion of Wnt proteins may have a biological effect on both the pre- and post-synaptic compartments.…”

Section: Synaptic Activity-regulated Wnt Signalingmentioning

confidence: 99%

Synaptic Activity-Regulated Wnt Signaling in Synaptic Plasticity, Glial Function and Chronic Pain

Tang¹

2014

CNSNDDT

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Wnt signaling pathways are master regulatory networks in a variety of developmental and oncogenic processes. In the nervous system, Wnt signaling pathways are known to regulate neuronal morphogenesis and synaptic differentiation. Aberrant Wnt signaling is implicated in various neurological diseases. Recent studies have revealed that the activity of Wnt signaling pathways is critically controlled by synaptic activity. The activity-regulated Wnt signaling plays an important role in the expression of synaptic plasticity and memory formation. Dysregulation of the activity-regulated Wnt signaling may have a significant impact on the function of the nervous system. In this article, we will review the identified mechanisms by which synaptic activity controls Wnt signaling in neurons and the neurological functions of the activity-regulated Wnt signaling under normal and specific disease conditions. In particular, we will discuss the role of Wnt signaling in the pathogenesis of chronic pain.

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Frizzled receptors in neurons: From growth cones to the synapse

Cited by 24 publications

References 37 publications

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

Spatio-Temporal Expression Pattern of Frizzled Receptors after Contusive Spinal Cord Injury in Adult Rats

Synaptic Activity-Regulated Wnt Signaling in Synaptic Plasticity, Glial Function and Chronic Pain

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