Localization of RNAi Machinery to Axonal Branch Points and Growth Cones Is Facilitated by Mitochondria and Is Disrupted in ALS

Gershoni-Emek, Noga; Altman, Topaz; Ionescu, Ariel; Costa, Christopher J.; Gradus-Pery, Tal; Willis, Dianna E.; Perlson, Eran

doi:10.3389/fnmol.2018.00311

Cited by 40 publications

(45 citation statements)

References 70 publications

(96 reference statements)

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“…Dicer is essential for the production of most~22nt active, mature miRNAs from short hairpin precursor miRNAs (pre-miRNAs) (Grishok et al, 2001;Hutvagner et al, 2001). Remarkably, several reports have revealed the presence of Dicer within growth cones (Hengst, 2006;Aschrafi et al, 2008;Zhang et al, 2013;Hancock et al, 2014;Kim et al, 2015;Vargas et al, 2016;Gershoni-Emek et al, 2018). These findings raise the intriguing possibility that inactive pre-miRNAs are trafficked along axons to the growth cone and locally activated to exert their function.…”

Section: Introductionmentioning

confidence: 99%

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

et al. 2020

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Various species of non‐coding RNAs (ncRNAs) are enriched in specific subcellular compartments, but the mechanisms orchestrating their localization and their local functions remain largely unknown. We investigated both aspects using the elongating retinal ganglion cell axon and its tip, the growth cone, as models. We reveal that specific endogenous precursor microRNAs (pre‐miRNAs) are actively trafficked to distal axons by hitchhiking primarily on late endosomes/lysosomes. Upon exposure to the axon guidance cue semaphorin 3A (Sema3A), pre‐miRNAs are processed specifically within axons into newly generated miRNAs, one of which, in turn, silences the basal translation of tubulin beta 3 class III (TUBB3), but not amyloid beta precursor protein (APP). At the organismal level, these mature miRNAs are required for growth cone steering and a fully functional visual system. Overall, our results uncover a novel mode of ncRNA transport from one cytosolic compartment to another within polarized cells. They also reveal that newly generated miRNAs are critical components of a ncRNA‐based signaling pathway that transduces environmental signals into the structural remodeling of subcellular compartments.

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Section: Introductionmentioning

confidence: 99%

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

et al. 2020

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“…Dicer and pre-miRNAs are present within axons Numerous studies have reported the presence of Dicer within mammalian growth cones by immunofluorescence in culture (Aschrafi et al, 2008;Gershoni-Emek et al, 2018;Hancock et al, 2014;Hengst et al, 2006;Kim et al, 2015b;Vargas et al, 2016;Zhang et al, 2013) , but whether Dicer is also detected in the growth cones of lower vertebrates such as Xenopus laevis is so far unknown. We thus examined the distribution of Dicer in RGC axons in this species (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Dicer is a key component of the miRNA-induced silencing complex (miRISC) which is essential for the production of~22 nt active, mature miRNAs from hairpin precursor miRNAs (pre-miRNAs) (Grishok et al, 2001;Hutvagner et al, 2001) . Remarkably, numerous reports have revealed the presence of Dicer within growth cones (Aschrafi et al, 2008;Gershoni-Emek et al, 2018;Hancock et al, 2014;Hengst et al, 2006;Kim et al, 2015b;Vargas et al, 2016;Zhang et al, 2013) . These findings raise the intriguing possibility that inactive pre-miRNAs are trafficked along axons to the growth cone and locally processed for function.…”

mentioning

confidence: 99%

Precursor miRNAs are trafficked along axons associated with vesicles and locally processed to regulate growth cone steering

Corradi

Gavoci

Strohbuecker

et al. 2018

Preprint

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AbstractVarious species of non-coding RNAs (ncRNAs) are enriched in subcellular compartments but the mechanisms orchestrating their delocalization and their local functions remain largely unknown. We investigated both aspects using the elongating retinal ganglion cell axon and its tip, the growth cone, as models. We reveal that specific endogenous precursor microRNAs (pre-miRNAs) are actively trafficked, anchored to CD63-positive vesicles, to distal axons along microtubules. Upon exposure to the chemotropic cue Sema3A, pre-miRNAs are processed specifically within axons into newly synthesized mature miRNAs, which, in turn, silence the basal translation of TUBB3 but not of APP. At the organismal level, these mature miRNAs are required for growth cone steering and a fully functional visual system. Overall, our results uncover a novel mode of ncRNA transport from one cytosolic compartment to another within polarized cells. They also reveal that newly synthesized miRNAs are critical components of a ncRNA-based signaling pathway that transduces environmental signals into the structural remodelling of subcellular compartments.HighlightsPrecursor miRNAs are actively transported along axons to the growth cone tethered to CD63-positive vesiclesSema3A but not Slit2 induces the local biogenesis of specific miRNAs within axonsMature miRNAs are important for growth cone responsiveness ex vivo and the establishment of functional connections in vivoNewly synthesized miRNAs inhibit the basal translation of TUBB3 but not APP upon Sema3A exposure

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“…In fact, miRISC protein GW182 was first identified from the serum auto-antibodies of patients with neuropathic symptoms (Eystathioy et al, 2002(Eystathioy et al, , 2003, and changes in its levels are implicated in Alzheimer's disease (Rouillard et al, 2016;Badhwar et al, 2017). Altered localization and trafficking of miRISC was recently reported in a cell culture model of amyotrophic lateral sclerosis (ALS) (Gershoni-Emek et al, 2018). Moreover, recent studies highlighting the interactions of miRISC components with proteins involved in neurodegenerative disorders, such as HTT, FUS, and Ataxin points toward an important role of miRISC composition in the pathology of these disease which should be investigated in detail (Savas et al, 2008;McCann et al, 2011;Zhang T. et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple components of miRISC machinery are shown to localize in developing axons and growth cones (Hengst et al, 2006;Murashov et al, 2007;Dajas-Bailador et al, 2012). A recent study has shown the co-localization of core miRISC (AGO2 and miRNAs) with mitochondria at axonal branch points and growth cone of peripheral nerve axons (Gershoni-Emek et al, 2018). miRISC protein FMRP has been shown to regulate Semaphorin 3A mediated growth cone collapse (Li, 2009).…”

Section: Polarization and Neurite Growthmentioning

confidence: 99%

The Role of Dynamic miRISC During Neuronal Development

Nawalpuri

Ravindran

Muddashetty

2020

Front. Mol. Biosci.

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Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development.

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Localization of RNAi Machinery to Axonal Branch Points and Growth Cones Is Facilitated by Mitochondria and Is Disrupted in ALS

Cited by 40 publications

References 70 publications

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

Precursor miRNAs are trafficked along axons associated with vesicles and locally processed to regulate growth cone steering

The Role of Dynamic miRISC During Neuronal Development

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