Wnt5a Mediates Nerve Growth Factor-Dependent Axonal Branching and Growth in Developing Sympathetic Neurons

Bodmer, Daniel; Levine-Wilkinson, Seamus; Richmond, Alissa; Hirsh, Sarah; Kuruvilla, Rejji

doi:10.1523/jneurosci.1445-09.2009

Cited by 78 publications

(101 citation statements)

References 51 publications

(64 reference statements)

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“…To investigate further if Rors mediate Wnt5a-dependent developmental processes in vivo, we analyzed Ror DKO embryos during a second stage of embryonic development in which the role of Wnt5a is well established. During nervous system development, expression of Wnt5a is induced in peripheral sympathetic neurons as their axons enter target organs (26). Wnt5a then signals in an autocrine manner to promote axon branching (26).…”

Section: Resultsmentioning

confidence: 99%

Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

Susman

Bikoff

et al. 2012

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

248

267

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Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor β-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a–Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a–Ror–Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development.

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Section: Resultsmentioning

confidence: 99%

Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

Susman

Bikoff

et al. 2012

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

248

267

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“…We quantified axonal branching by measuring the axonal branch number of different branching orders. 25 Neurons overexpressing JNK3 CS showed more branches at all branching orders (secondary, 6.5 ± 0.3, Po0.01; tertiary, 2.7 ± 0.2, Po0.01; higher, 0.4 ± 0.1, Po0.01) and doubled the total branch number, compared with neurons with DsRed2 alone (secondary, 3.3 ± 0.2; tertiary, 0.7 ± 0.1; higher, 0.0 ± 0.0) or JNK3 WT (secondary, 3.8 ± 0.2; tertiary, 0.8 ± 0.2; higher, 0.0 ± 0.0) (Figure 2c). Moreover, compared with controls, JNK3 CS induced a significant increase in total branch length (Figure 2c), although the length of the primary axon decreased.…”

Section: Resultsmentioning

confidence: 99%

Isoform-specific palmitoylation of JNK regulates axonal development

et al. 2011

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The c-jun N-terminal kinase (JNK) proteins are encoded by three genes (Jnk1-3), giving rise to 10 isoforms in the mammalian brain. The differential roles of JNK isoforms in neuronal cell death and development have been noticed in several pathological and physiological contexts. However, the mechanisms underlying the regulation of different JNK isoforms to fulfill their specific roles are poorly understood. Here, we report an isoform-specific regulation of JNK3 by palmitoylation, a posttranslational modification, and the involvement of JNK3 palmitoylation in axonal development and morphogenesis. Two cysteine residues at the COOH-terminus of JNK3 are required for dynamic palmitoylation, which regulates JNK3's distribution on the actin cytoskeleton. Expression of palmitoylation-deficient JNK3 increases axonal branching and the motility of axonal filopodia in cultured hippocampal neurons. The Wnt family member Wnt7a, a known modulator of axonal branching and remodelling, regulates the palmitoylation and distribution of JNK3. Palmitoylation-deficient JNK3 mimics the effect of Wnt7a application on axonal branching, whereas constitutively palmitoylated JNK3 results in reduced axonal branches and blocked Wnt7a induction. Our results demonstrate that protein palmitoylation is a novel mechanism for isoform-specific regulation of JNK3 and suggests a potential role of JNK3 palmitoylation in modulating axonal branching. The c-jun N-terminal kinase (JNK) family consists of JNK1, JNK2 and JNK3 subgroups, which participate in diverse biological and pathological processes. 1,2 At least 10 JNK isoforms of varied sizes, with most between 46 and 54 kDa, are produced from the Jnk1-3 genes, giving rise to JNK isoforms. 1 In the nervous system, JNKs (particularly isoform JNK3) have been extensively studied as the key players in apoptosis and neurodegeneration. [3][4][5][6] However, accumulating evidence supports a physiological role of JNK in regulating neurite formation and morphogenesis. 7-12 Pharmacological inhibition of JNK activity blocks axogenesis in hippocampal neurons, arguing for an essential role of JNK in neurite development. 13 Growth factors and signalling molecules, including secreted proteins of the Wnt family, have also been found to activate JNK for remodelling dendrites and axons, a process that relies on cytoskeletal rearrangement. 11,[14][15][16] This has led to the identification of several actin-or microtubule-associated proteins as JNK substrates that modulate different aspects of cytoskeletal activity. 17 However, all the 10 JNK isoforms share the same kinase domain and activation mechanism. 17 The differential roles of JNK isoforms in neurite development and the mechanisms underlying isoform-specific regulation are poorly understood.Analysis of animals null for particular JNK isoforms provides the first evidence to support isoform-specific roles of JNKs in the brain. Mice with Jnk1 À/À show abnormalities in neurite development, 7 whereas mice null for Jnk1 and Jnk2 show embryonic lethality due to severe neuro...

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“…SCG explants were cultured as described previously (34). Where indicated, explants were pre-incubated with 200 nM compound E (Calbiochem) and 1 M c29 peptide or scrambled peptide before addition of 10 ng/ml NGF (Biosensis).…”

Section: Methodsmentioning

confidence: 99%

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

Matusica

Skeldal

Sykes

et al. 2013

Journal of Biological Chemistry

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Background:The mechanism by which the p75 neurotrophin receptor (p75 NTR ) and TrkA interact to enhance neurotrophin signaling is unknown. Results: The p75NTR intracellular domain fragment, p75 ICD , but not full-length p75 NTR enhanced NGF binding to TrkA and neurite outgrowth. Conclusion:The results suggest that p75 ICD causes a conformational change within the extracellular domain of TrkA. Significance: The findings challenge our current understanding of how p75 NTR enhances neurotrophic activity.

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Wnt5a Mediates Nerve Growth Factor-Dependent Axonal Branching and Growth in Developing Sympathetic Neurons

Cited by 78 publications

References 51 publications

Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

Isoform-specific palmitoylation of JNK regulates axonal development

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

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