The Wnt Antagonist, Dickkopf-1, as a Target for the Treatment of Neurodegenerative Disorders

Caraci, Filippo; Busceti, Carla L.; Biagioni, Francesca; Aronica, Eleonora; Mastroiacovo, Federica; Cappuccio, I.; Battaglia, Giuseppe; Bruno, Valeria; Caricasole, Andrea; Copani, Agata; Nicoletti, Ferdinando

doi:10.1007/s11064-008-9710-0

Cited by 58 publications

(43 citation statements)

References 56 publications

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“…[46][47][48] Our results are in accord with the increasingly accepted role for Wnts in the modulation of fundamental aspects of the homeostasis and neuronal function of the adult CNS. 14,17,18,[49][50][51][52][53] In this line of thought, we provide supporting evidences of previous reports describing the expression of most Wnt ligands and receptors by PCR 39 and in situ hybridization analysis, 35 as well as a constitutive active b-catenin-mediated transcription in the dorsal horns and the central canal of the adult spinal cord of mice. 22,32 Interestingly, Wnt3a and Wnt5a have been recently described to be expressed by neurons of the ventral and dorsal horn of adult mice, and that the latter received Wnt3a and Wnt5a synapsis from dorsal root ganglia sensory neurons, with at least involvement of the b-catenin pathway, as evidenced by its enrichment in the pre-and postsynaptic contacts.…”

Section: Discussionsupporting

confidence: 90%

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Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

González-Fernández

Fernández-Martos

Shields

et al. 2014

Journal of Neurotrauma

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The Wnt family of proteins plays key roles during central nervous system development and has been involved in several neuropathologies during adulthood, including spinal cord injury (SCI). However, Wnts expression knowledge is relatively limited during adult stages. Here, we sought to define the Wnt family expression pattern after SCI in adult mice by using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Under physiological conditions, the messenger RNAs (mRNAs) of most Wnt ligands, inhibitors, receptors, and coreceptors are constitutively expressed in healthy adult mice. After dorsal hemisection, we found significant time-dependent variations, with a prominent upregulation of Wnt inhibitory factor 1 (Wif1). IHC against Frizzled (Fz) 1 and Fz4, as representatives of late and acute upregulated receptors, showed a differential expression in the uninjured spinal cord of Fz1 by neurons and oligodendrocytes and Fz4 by astrocytes. After injury, both receptors were maintained in the same type of cells. Finally, by using BATgal reporter mice, our results revealed active b-catenin signaling in neurons of the dorsal horn and cells of the central canal of uninjured spinal cords, besides a lack of additional SCI-induced activation.In conclusion, we demonstrate Wnt expression in the adult spinal cord of mice that is modulated by SCI, which differs from that previously described in rats. Further, Fz receptors are differentially expressed by neurons and glial cells, suggestive for cell-specific patterns and thus diverse physiological roles. Further studies will help toward in-depth characterization of the role of all Wnt factors and receptors described and eventually allow for the design of novel therapies.

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Section: Discussionsupporting

confidence: 90%

“…A growing body of evidence suggests that Wnt signaling may be involved in homeostasis and disease progression in adult tissues, [17][18][19][20][21][22][23][24][25][26] including the spinal cord.…”

mentioning

confidence: 99%

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

González-Fernández

Fernández-Martos

Shields

et al. 2014

Journal of Neurotrauma

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“…10,46 Acyl modification of Wnt proteins was also shown to have a crucial role for proteins exiting from the endoplasmic reticulum, secreting to the extracellular domain or binding to the receptor. 21,22 Thus a regulatory mechanism of protein acylation may be necessary for cells to control Wnt/β-catenin signaling activity.…”

Section: Discussionmentioning

confidence: 99%

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Hsu

Chan

et al. 2014

Cell Death Differ

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The Wnt/β-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/β-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/β-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelialmesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/β-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/β-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.

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“…2 Although currently there are no data regarding Ryk functions in oligodendroglial cell death, it should be noted that several reports have shown that, after a CNS injury, the Wnt family of proteins is able to modulate cell survival in other neural cell types, such as neurons. 6,20 Finally, an interesting point of discussion derives from the presence of fibronectin + cells in the lesion epicenter. Several reports have demonstrated the presence of fibronectin in the injury core, even in non-penetrating injuries where meningeal fibroblast invasion and proliferation are minimal.…”

Section: Fig 7 Ryk Is Expressed In Fibronectinmentioning

confidence: 99%

“…[3][4][5] A growing body of evidence suggests that Wnt signalling may be involved in homeostasis and disease progression in adult tissues, [6][7][8][9][10][11] including the spinal cord. 10,[12][13][14][15][16] Consistent with these findings, we have previously shown that most of Wnt ligands and inhibitors are expressed in the adult spinal cord of rats and, following SCI, are differentially induced with at least Wnt/b-catenin signalling activation in cells that appear to be involved in glial scarring.…”

mentioning

confidence: 99%

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

González

Fernández-Martos

Arenas

et al. 2013

Journal of Neurotrauma

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Wnt proteins play a critical role in central nervous system development and have been implicated in several neuropathologies, including spinal cord injury (SCI). Ryk, an unconventional Wnt receptor, regulates axonal regeneration after SCI, although its expression pattern in this neuropathology remains unclear. Therefore, we sought to define the spatiotemporal and cellular pattern of Ryk expression after a contusive SCI in adult rats using quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis. Under physiological conditions, Ryk is expressed in neurons, astrocytes, and blood vessels, but not in oligodendrocytes, microglia, NG2+ glial precursor cells, or axonal projections. Following SCI, we observed an increase in Ryk mRNA expression from 24 h post-injury until 7 days post-injury, whereas its protein levels were significantly augmented at 7 and 14 days post-injury. Moreover, the spatial and cellular Ryk expression pattern was altered in the damaged tissue, where this receptor was observed in reactive astrocytes and microglia/macrophages, NG2+ glial precursors, fibronectin + cells, oligodendrocytes, and axons. In conclusion, we demonstrate that Ryk is expressed in the unlesioned spinal cord and that, after SCI, its spatiotemporal and cellular expression pattern changed dramatically, being expressed in cells involved in the spinal cord response to damage.

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The Wnt Antagonist, Dickkopf-1, as a Target for the Treatment of Neurodegenerative Disorders

Cited by 58 publications

References 56 publications

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

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