A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

Vidaki, Marina; Drees, Frauke; Saxena, Tanvi; Lanslots, Erwin; Taliaferro, J. Matthew; Tatarakis, Antonios; Burge, Christopher B.; Wang, Eric T.; Gertler, Frank B.

doi:10.1016/j.neuron.2017.06.048

Cited by 40 publications

(40 citation statements)

References 90 publications

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“…Next, to capture the targets of CELF6 in vivo, we chose a region approximately 60-200 nucleotides in size (80-150 kDa) to purify from lysates of 4 pools of CELF6-YFP/HA+ brains. Similar to Vidaki et al's study of Mena (25), we found that the stringent lysis and wash conditions of standard CLIP protocols were incompatible with CELF6 IP (not shown). Therefore, to enable rigorous statistical definitions of CLIP targets, we also collected 4 replicates of CLIP samples generated from pools of 3-4 brains from 4 independent litters, and a key additional control:.…”

Section: Celf6 Primarily Associates With 3'utrs Of Target Mrnas In Vivosupporting

confidence: 88%

CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo

Rieger

King

Cohen

et al. 2018

Preprint

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CELF6 is an RNA-binding protein in a family of proteins with roles in human health and disease, however little is known about the mRNA targets or in vivo function of this protein.We utilized HITS-CLIP/CLIP-Seq to identify, for the first time, in vivo targets of CELF6 and identify hundreds of transcripts bound by CELF6 in the brain. We found these are disproportionately mRNAs coding for synaptic proteins. We then conducted extensive functional validation of these targets, testing greater than 400 CELF6 bound sequence elements for their activity, applying a massively parallel reporter assay framework to evaluation of the CLIP data. We also mutated every potential CELF6 binding motif within these elements and tested their impact. This comprehensive analysis led us to ascribe a previously unknown function to CELF6: we found bound elements were generally repressive of translation, that CELF6 further enhances this repression via decreasing RNA abundance, and this process was dependent on UGU-rich sequence motifs. This greatly extends the known role for CELF6, which had previously been defined only as a splicing factor. We further extend these findings by demonstrating the same function for CELF3, CELF4, and CELF5. Finally, we demonstrate that the CELF6 targets are derepressed in CELF6 mutant mice in vivo, confirming this new role in the brain. Thus, our study demonstrates that CELF6 and other sub-family members are repressive CNS RNA-binding proteins, and CELF6 downregulates specific mRNAs in vivo.

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Section: Celf6 Primarily Associates With 3'utrs Of Target Mrnas In Vivosupporting

confidence: 88%

CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo

Rieger

King

Cohen

et al. 2018

Preprint

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“…CYFIP2 has homology with the translation repressors, the eIF4E binding proteins (eIF4E-BPs) ( Napoli et al., 2008 ), and can potentially help to silence mRNA translation as the RNP is trafficked along the axon. Interestingly, like CYFIP, Mena has recently been shown to have a dual function in regulating both actin polymerization and mRNA translation ( Vidaki et al., 2017 ). Mena, but not its paralogs VASP and EVL, associates with a specific set of mRNAs and is a key regulator of Dyrk1a synthesis in axons in response to BDNF stimulation ( Vidaki et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function

Cioni

Wong

Bressan

et al. 2018

Neuron

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SummaryThe axons of retinal ganglion cells (RGCs) are topographically sorted before they arrive at the optic tectum. This pre-target sorting, typical of axon tracts throughout the brain, is poorly understood. Here, we show that cytoplasmic FMR1-interacting proteins (CYFIPs) fulfill non-redundant functions in RGCs, with CYFIP1 mediating axon growth and CYFIP2 specifically involved in axon sorting. We find that CYFIP2 mediates homotypic and heterotypic contact-triggered fasciculation and repulsion responses between dorsal and ventral axons. CYFIP2 associates with transporting ribonucleoprotein particles in axons and regulates translation. Axon-axon contact stimulates CYFIP2 to move into growth cones where it joins the actin nucleating WAVE regulatory complex (WRC) in the periphery and regulates actin remodeling and filopodial dynamics. CYFIP2’s function in axon sorting is mediated by its binding to the WRC but not its translational regulation. Together, these findings uncover CYFIP2 as a key regulatory link between axon-axon interactions, filopodial dynamics, and optic tract sorting.

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“…The findings show clearly that hMENA 11a transfection in cells that do not contain this isoform inhibits different ECM proteins. In view of the recent published results on the novel role for Mena in the regulation of local translation of specific mRNAs in developing axons, including FN1 mRNA, it could be posited that hMENA 11a restrains the posttranscriptional effect of hMENA [ 55 ]. Our data show that hMENA 11a inhibits the secretion of β1 integrin ligand collagens, laminin, and fibronectin (Fig.…”

Section: Discussionmentioning

confidence: 99%

hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis

Modugno¹,

Spada

Palermo³

et al. 2018

Oncogene

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We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA11a and hMENAΔv6, which have opposite functions in cell invasiveness. Their mechanisms of action have remained unclear. Here we report two major findings: (i) hMENA regulates β1 integrin expression. This was shown by depleting total hMENA, which led to loss of nuclear expression of serum response factor (SRF)-coactivator myocardin-related transcription factor 1 (MRTF-A), leading to an increase in the G-actin/F-actin ratio crucial for MRTF-A localization. This in turn inhibited SRF activity and the expression of its target gene β1 integrin. (ii) hMENA11a reduces and hMENAΔv6 increases β1 integrin activation and signaling. Moreover, exogenous expression of hMENA11a in hMENAΔv6-positive cancer cells dramatically reduces secretion of extracellular matrix (ECM) components, including β1 integrin ligands and metalloproteinases. On the other hand, overexpression of the pro-invasive hMENAΔv6 increases fibronectin production. In primary tumors high hMENA11a correlates with low stromal fibronectin and a favorable clinical outcome of early node-negative non-small-cell lung cancer patients. These data provide new insights into the roles of hMENA11a and hMENAΔv6 in the druggable β1 integrin-ECM signaling axis and allow stratification of patient risk, guiding their clinical management.

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A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

Cited by 40 publications

References 90 publications

CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo

CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo

Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function

hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis

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