Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation

Feltrin, Daniel; Fusco, Ludovico; Witte, Harald; Moretti, Francesca; Martin, Katrin; Letzelter, Michel; Fluri, Erika; Scheiffele, Peter; Pertz, Olivier

doi:10.1371/journal.pbio.1001439

Cited by 46 publications

(86 citation statements)

References 54 publications

(84 reference statements)

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“…This model recapitulates the extension of neurites before axon-dendrite specification, which is the principal morphological characteristic of early neuronal differentiation (12). Using this model, we demonstrated that local mRNA translation not only is a feature of axons and dendrites but also occurs at early neuronal differentiation stages (9).…”

mentioning

confidence: 60%

“…Mouse N1E-115 cells (American Tissue Culture Collection; cell line established by cloning the C-1300 spontaneous mouse neuroblastoma tumor) were cultured and transfected as previously described (9). For Hmgn5 knockdown (KD), cells were transfected with 80 nM small interfering RNA (siRNA; Dharmacon siRNA SMARTpool Plus or a single Dharmacon siRNA [J-044143-05] for rescue experiments).…”

Section: Methodsmentioning

confidence: 99%

“…We previously identified ϳ80 mRNAs localizing to the extending neurites of neuron-like N1E-115 cells (9), a mouse neuroblastoma cell line widely used as an in vitro system to study neuronal differentiation (10,11). This model recapitulates the extension of neurites before axon-dendrite specification, which is the principal morphological characteristic of early neuronal differentiation (12).…”

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confidence: 99%

“…Among the neurite-enriched mRNAs in N1E-115 cells, we identified transcripts encoding nuclear proteins (9). One of these mRNAs encodes the high-mobility group N5 (HMGN5) chromatin binding protein.…”

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confidence: 99%

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Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth

Moretti

Rolando

Winker

et al. 2015

Molecular and Cellular Biology

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f Neurons exploit local mRNA translation and retrograde transport of transcription factors to regulate gene expression in response to signaling events at distal neuronal ends. Whether epigenetic factors could also be involved in such regulation is not known. We report that the mRNA encoding the high-mobility group N5 (HMGN5) chromatin binding protein localizes to growth cones of both neuronlike cells and of hippocampal neurons, where it has the potential to be translated, and that HMGN5 can be retrogradely transported into the nucleus along neurites. Loss of HMGN5 function induces transcriptional changes and impairs neurite outgrowth, while HMGN5 overexpression induces neurite outgrowth and chromatin decompaction; these effects are dependent on growth cone localization of Hmgn5 mRNA. We suggest that the localization and local translation of transcripts coding for epigenetic factors couple the dynamic neuronal outgrowth process with chromatin regulation in the nucleus.

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confidence: 60%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth

Moretti

Rolando

Winker

et al. 2015

Molecular and Cellular Biology

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“…The DLK/JNK pathway is known to regulate microtubule organization and stability (Hirai et al, 2002(Hirai et al, , 2006(Hirai et al, , 2011Lewcock et al, 2007;Eto et al, 2010;Hendricks and Jesuthasan, 2009;Feltrin et al, 2012;Ghosh-Roy et al, 2012), but its specific effect on the transition from motile growth cone to stable bouton has not been examined. Having established that increased Wnd disrupts this transition, we wanted to determine the mechanism in more detail.…”

Section: Resultsmentioning

confidence: 99%

Wallenda/DLK protein levels are temporally downregulated by Tramtrack69 to allow R7 growth cones to become stationary boutons

Feoktistov

Herman

2016

Development

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Dual leucine zipper kinase (DLK) promotes growth cone motility and must be restrained to ensure normal development. PHR (Pam/ Highwire/RPM-1) ubiquitin ligases therefore target DLK for degradation unless axon injury occurs. Overall DLK levels decrease during development, but how DLK levels are regulated within a developing growth cone has not been examined. We analyzed the expression of the fly DLK Wallenda (Wnd) in R7 photoreceptor growth cones as they halt at their targets and become presynaptic boutons. We found that Wnd protein levels are repressed by the PHR protein Highwire (Hiw) during R7 growth cone halting, as has been observed in other systems. However, as R7 growth cones become boutons, Wnd levels are further repressed by a temporally expressed transcription factor, Tramtrack69 (Ttk69). Previously unobserved negative feedback from JNK also contributes to Wnd repression at both time points. We conclude that neurons deploy additional mechanisms to downregulate DLK as they form stable, synaptic connections. We use live imaging to probe the effects of Wnd and Ttk69 on R7 bouton development and conclude that Ttk69 coordinates multiple regulators of this process.

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Alternative polyadenylation in the nervous system: To what lengths will 3′ UTR extensions take us?

et al. 2014

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Alternative cleavage and polyadenylation (APA) can diversify coding and non-coding regions, but has particular impact on increasing 3′ UTR diversity. Through the gain or loss of regulatory elements such as RNA binding protein and microRNA sites, APA can influence transcript stability, localization, and translational efficiency. Strikingly, the central nervous systems of invertebrate and vertebrate species express a broad range of transcript isoforms bearing extended 3′ UTRs. The molecular mechanism that permits proximal 3′ end bypass in neurons is mysterious, and only beginning to be elucidated. This landscape of neural 3′ UTR extensions, many reaching unprecedented lengths, may help service the unique post-transcriptional regulatory needs of neurons. A combination of approaches, including transcriptome-wide profiling, genetic screening to identify APA factors, biochemical dissection of alternative 3′ end formation, and manipulation of individual neural APA targets, will be necessary to gain fuller perspectives on the mechanism and biology of neural-specific 3′ UTR lengthening.

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Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation

Abstract: Growth cone localization of MKK7 mRNA switches the classic function of MKK7 protein in transcriptional control to regulation of microtubules necessary for neuronal outgrowth.

Cited by 46 publications

References 54 publications

Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth

Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth

Wallenda/DLK protein levels are temporally downregulated by Tramtrack69 to allow R7 growth cones to become stationary boutons

Alternative polyadenylation in the nervous system: To what lengths will 3′ UTR extensions take us?

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