Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

Martínez, José C.; Randolph, Lisa K.; Iascone, Daniel Maxim; Pernice, Helena F.; Polleux, Franck; Hengst, Ulrich

doi:10.1016/j.neuron.2019.08.035

Cited by 39 publications

(38 citation statements)

References 63 publications

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“…One possibility is the stagespecific regulation of axonal vs. dendritic mRNA trafficking resulting from the expression of particular RBPs. For example, the association of the RBPs Pumilio (Pum) 1 and 2 with mRNAs containing 3 -UTR Pumilio binding elements (PBEs) prevents these transcripts from entering axons during development (Shigeoka et al, 2016;Martínez et al, 2019). Genetic loss of Pum2 causes many mRNAs with PBEs to mislocalize into developing axons and Pum2 knock-down mice have impaired axon outgrowth and branching during postnatal callosal pathway development (Martínez et al, 2019).…”

Section: Local Transcriptomes/translatomes Are Remodeled During Circumentioning

confidence: 99%

A Picture Worth a Thousand Molecules—Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits

Minehart

Speer

2021

Front. Synaptic Neurosci.

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A key challenge in developmental neuroscience is identifying the local regulatory mechanisms that control neurite and synaptic refinement over large brain volumes. Innovative molecular techniques and high-resolution imaging tools are beginning to reshape our view of how local protein translation in subcellular compartments drives axonal, dendritic, and synaptic development and plasticity. Here we review recent progress in three areas of neurite and synaptic study in situ—compartment-specific transcriptomics/translatomics, targeted proteomics, and super-resolution imaging analysis of synaptic organization and development. We discuss synergies between sequencing and imaging techniques for the discovery and validation of local molecular signaling mechanisms regulating synaptic development, plasticity, and maintenance in circuits.

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Section: Local Transcriptomes/translatomes Are Remodeled During Circumentioning

confidence: 99%

A Picture Worth a Thousand Molecules—Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits

Minehart

Speer

2021

Front. Synaptic Neurosci.

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“…Deficiencies in several RBPs other than FMRP have been associated with epilepsy, including BRUNOL4/CELF4 [ 210 ], RBFOX1 [ 211 ], and Pumilio2 [ 212 ]. Of these, Pumilio2 is suggested to affect LPS: it is present in dendritic stress granules during metabolic stress [ 213 ] and has recently also been reported to influence the transcriptome of the developing axon by somatic retention of certain mRNAs [ 214 ]. Other RBPs implicated in epilepsy are known to be regulated by the translation initiation-promoting mTOR/MAPK pathway, pharmacological inhibition of which effectively prevents epileptogenesis [ 215 ].…”

Section: Establishment Of Axon Architecture and Connectivitymentioning

confidence: 99%

Axonal mRNA translation in neurological disorders

2020

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It is increasingly recognized that local protein synthesis (LPS) contributes to fundamental aspects of axon biology, in both developing and mature neurons. Mutations in RNA-binding proteins (RBPs), as central players in LPS, and other proteins affecting RNA localization and translation are associated with a range of neurological disorders, suggesting disruption of LPS may be of pathological significance. In this review, we substantiate this hypothesis by examining the link between LPS and key axonal processes, and the implicated pathophysiological consequences of dysregulated LPS. First, we describe how the length and autonomy of axons result in an exceptional reliance on LPS. We next discuss the roles of LPS in maintaining axonal structural and functional polarity and axonal trafficking. We then consider how LPS facilitates the establishment of neuronal connectivity through regulation of axonal branching and pruning, how it mediates axonal survival into adulthood and its involvement in neuronal stress responses.

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“…Similar results were also recently obtained in DRG neurons. Here, the RBP Pumilio 2 was observed to be restricted to neuronal cell bodies, where it regulates the axonal transcriptome through somatic retention of a specific subset of transcripts; a process developmentally regulated and essential for proper axonal outgrowth and regeneration [82].…”

Section: Rbps Regulating Mrna Localization In Axonsmentioning

confidence: 99%

“…While specific axonal mRNA targeting signals remain poorly understood, in the reverse direction of inquiry, a cis-acting element was recently identified to keep mRNA out of axons. Here, Martínez et al [ 82 ] employed a bioinformatics approach to look at sequences associated with the axonal versus somatodendritic transcriptome. Although the authors found no sequence motifs associated with the axonal transcriptome, a UGUAAAU motif was discovered as enriched within the somatodendritic transcriptome.…”

Section: Mrna Features That Drive Their Axonal Localizationmentioning

confidence: 99%

“…Although the authors found no sequence motifs associated with the axonal transcriptome, a UGUAAAU motif was discovered as enriched within the somatodendritic transcriptome. When inserted into ordinarily axonally localized transcripts this motif was able to diminish axonal localization; the RBP responsible was identified to be Pumilio 2 [ 82 ]. In the future, new techniques, such as ‘proximity-CLIP’, [ 130 ] might be able to help us further decipher how differences in protein–RNA interactions lead to altered mRNA localization patterns between axons, dendrites and soma.…”

Section: Mrna Features That Drive Their Axonal Localizationmentioning

confidence: 99%

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Molecular mechanisms behind mRNA localization in axons

2020

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Messenger RNA (mRNA) localization allows spatiotemporal regulation of the proteome at the subcellular level. This is observed in the axons of neurons, where mRNA localization is involved in regulating neuronal development and function by orchestrating rapid adaptive responses to extracellular cues and the maintenance of axonal homeostasis through local translation. Here, we provide an overview of the key findings that have broadened our knowledge regarding how specific mRNAs are trafficked and localize to axons. In particular, we review transcriptomic studies investigating mRNA content in axons and the molecular principles underpinning how these mRNAs arrived there, including cis-acting mRNA sequences and trans-acting proteins playing a role. Further, we discuss evidence that links defective axonal mRNA localization and pathological outcomes.

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Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

Cited by 39 publications

References 63 publications

A Picture Worth a Thousand Molecules—Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits

A Picture Worth a Thousand Molecules—Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits

Axonal mRNA translation in neurological disorders

Molecular mechanisms behind mRNA localization in axons

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