ELAV-like protein 4 · UniProt P26378
ELAVL4/HuD is a neuron-enriched RNA-binding protein that governs post-transcriptional control of mRNAs underlying neuronal differentiation, axon and dendrite growth, and synaptic plasticity (PMID:11259113, PMID:24599466). It uses three RNA recognition motifs to bind AU-rich and U-rich elements: RRM1 and RRM2 contribute most of the affinity and engage clustered AUUUA repeats through base-recognition pockets resolved by crystal structures, while all three RRMs cooperate, and HuD intrinsically prefers U-rich tracts (PMID:8626712, PMID:10848602, PMID:11175903, PMID:12900401). Functionally, HuD stabilizes target transcripts by binding 3'UTR AREs and slowing deadenylation — demonstrated for GAP-43, AChE, neuroserpin, MYCN, BDNF long-3'UTR isoforms, APP/BACE1, and SOD1 — and its stabilizing activity scales with poly(A) tail length (PMID:11711535, PMID:12034726, PMID:12468554, PMID:12000840, PMID:16405504, PMID:17234598, PMID:24857657, PMID:23383270, PMID:33271327). Beyond stabilization, HuD enhances cap-dependent translation by directly binding eIF4A and poly(A), an activity required for neurite outgrowth (PMID:20064466). HuD shuttles between nucleus and cytoplasm via a linker-region NES, localizes to actin-dependent RNA granules in growth cones and dendrites, and undergoes activity-dependent dendritic targeting alongside translational machinery (PMID:10620013, PMID:12957493, PMID:15519747, PMID:18769135). Its activity is tuned by CARM1-mediated arginine methylation (reducing mRNA stabilization), the Y3 small non-coding RNA acting as a dominant molecular sponge, and miR-375/miR-129 regulation (PMID:16508003, PMID:30029004, PMID:20584986). Through a Tudor-domain-dependent interaction with SMN, HuD supports axonal localization of mRNAs such as cpg15 and GAP-43, and HuD overexpression rescues SMN-deficiency motoneuron defects, linking it to spinal muscular atrophy pathology (PMID:21088113, PMID:21389246, PMID:21652774, PMID:29061699). In ALS, mutant FUS and FMRP competition elevate HuD, overstabilizing NRN1 and GAP43 and dysregulating axon growth, and HuD co-aggregates with FUS in patient tissue (PMID:31242416, PMID:34471224). In non-neuronal pancreatic β-cells HuD controls insulin translation, ATG5-dependent autophagosome formation, and Mfn2-mediated mitochondrial fusion (PMID:22387028, PMID:24275661, PMID:31659282).
Established HuD as a candidate neuron-specific RNA-processing factor by identifying its three RRM domains and homology to ELAV-family proteins.
Evidence cDNA cloning and sequence analysis
Resolved which domains drive RNA recognition, showing HuD binds AU-rich elements and that RRM1/RRM2 are essential, defining the biochemical basis of target recognition.
Evidence Purified protein RNA-binding assays with deletion mutants
Refined the binding model with quantitative kinetics, showing all three RRMs cooperate and a conformational change stabilizes the RNA complex.
Evidence Surface plasmon resonance with deletion mutants
Provided atomic-resolution recognition rules by crystallizing RRM1/RRM2 with two ARE RNAs, defining base-recognition pockets and the central-uracil requirement.
Evidence X-ray crystallography of HuD-ARE complexes
Established HuD's intrinsic U-rich sequence preference and minimal binding-site length through unbiased selection.
Evidence SELEX and equilibrium binding with deletion mutants
Defined the core stabilization mechanism — HuD slows deadenylation and prefers long poly(A) tails — connecting binding to extended mRNA half-life for GAP-43, AChE, and neuroserpin.
Evidence In vitro decay assays, overexpression, recombinant protein addition in PC12/neuronal cells
PMID:11711535 PMID:12000840 PMID:12034726 PMID:12468554
Linked HuD localization to function by identifying a linker-region NES required for nucleocytoplasmic shuttling and neurite induction.
Evidence Deletion/dominant-negative mutants in PC12 and P19 differentiation assays
Placed HuD in nuclear export and dendritic RNP transport, identifying TAP/NXF1, IMP-1, G3BP-1, and ribosome co-localization as a transport/translation context.
Evidence Recombinant binding, RNA-dependent co-IP, fractionation, confocal imaging
PMID:12957493 PMID:15086518 PMID:15358174 PMID:15519747
Identified post-translational control of HuD: CARM1 arginine methylation reduces its mRNA-stabilizing activity, coupling differentiation timing to HuD modification, and confirmed in vivo stabilization of GAP-43 in transgenic mice.
Evidence In vitro methylation, siRNA, methylation-resistant mutants, transgenic mice
Demonstrated physiological relevance in injury, showing axotomy reduces HuD-AChE binding and that HuD restoration maintains target mRNA levels.
Evidence In vitro decay assays and HSV-HuD in vivo rescue in ganglion neurons
Connected HuD to activity-dependent synaptic plasticity through NMDAR-dependent dendritic targeting and association with plasticity mRNAs and translation factors.
Evidence RNA-IP, KCl stimulation, NMDAR1 knockout analysis, immunofluorescence
Revealed a second mechanism — direct translational enhancement via eIF4A and poly(A) binding — and expanded the genome-wide target repertoire including U-rich and C-rich motifs.
Evidence In vitro translation with HCV IRES controls, eIF4A co-IP, binding mutants, mRNP-IP microarray
Established HuD's regulation and autoregulation: miR-375 represses HuD, Hu proteins autoregulate their own exon-6 splicing, and CARM1 methylation modulates target binding.
Evidence Reporter assays, minigene splicing, miRNA/HuD overexpression in hippocampus
PMID:16508003 PMID:20159993 PMID:20584986
Defined the SMN-HuD axis as a motor-neuron mRNA transport pathway, with Tudor-domain-dependent binding, SMA-linked mutations disrupting it, axonal cargo (cpg15, poly(A) mRNA) dependence, and zebrafish rescue.
Evidence BiFC, pulldown with Tudor mutants, mass spec, co-IP, SMN knockdown, zebrafish rescue
PMID:21088113 PMID:21389246 PMID:21652774
Extended HuD function to non-neuronal β-cells, showing it represses Ins2 translation via a 5'UTR site in a glucose-responsive manner.
Evidence RIP, gain/loss-of-function, insulin assays, KO/OE mice, glucose treatment
Broadened HuD's functional reach across mTORC1-linked translation, axonal mRNA localization with ZBP1, isoform-selective BDNF stabilization, β-cell autophagy via ATG5, and APP/BACE1 stabilization relevant to Alzheimer pathology.
Evidence RIP, decay/stability assays, co-IP, ARE mutagenesis, mTORC1 inhibition, transgenic and KO mice
PMID:23383270 PMID:23586486 PMID:23836929 PMID:24275661 PMID:24857657
Defined the in vivo developmental requirement for HuD via conditional knockout, linking loss to dendritogenesis, cortical specification, learning, and seizure-susceptibility phenotypes.
Evidence Conditional KO mice, morphometry, behavioral testing
Placed HuD in regulatory circuits driving neuronal differentiation and branch-specific dendritic translation, including a HuD-SATB1 feedback loop and poly(A)-tail-dependent CaMKIIα capture, with PKC phosphorylation promoting dendritic BDNF translation.
Evidence Knockdown/overexpression, mRNA stability and rescue assays, RRM3-deletion and phospho-mutants, branch imaging
PMID:25692578 PMID:25944900 PMID:26152301 PMID:26305964
Established a metabolic role for HuD in β-cells by promoting INSIG1 translation and thereby restraining SREBP1c-driven lipogenesis.
Evidence RIP, pulldown, gain/loss-of-function, SREBP1c localization, KO mice
Reframed HuD regulation by showing the Y3 small non-coding RNA is its dominant interactor and acts as a molecular sponge limiting HuD recruitment to polysomes and translation enhancement.
Evidence CLIP-seq, polysome profiling, Y3 sponge functional assays
Implicated HuD in ALS, showing mutant FUS shifts to ELAVL4 3'UTR raising HuD, co-aggregation with FUS in stress granules and patient tissue, and HuD-dependent mitochondrial fusion via Mfn2 in β-cells.
Evidence CLIP-seq, iPSC motor neurons, co-IP/co-localization, patient tissue; RIP and rescue for Mfn2
Detailed translational control of ELAVL4 itself and of SOD1, showing Celf1-regulated 5'UTR isoform translation governs neuron development and oxidative-stress-driven APA enhances HuD-SOD1 binding, elevated in sporadic ALS.
Evidence Polysome RNA-seq, 5'UTR reporters, Celf1 manipulation; binding/decay assays, APA analysis, patient RIP
Defined a mechanistic ALS pathway in which mutant FUS and FMRP compete for HuD mRNA, elevating HuD and overstabilizing NRN1/GAP43 to dysregulate axon growth, rescuable by lowering NRN1.
Evidence iPSC motor neurons and mouse models, RIP, competition and rescue assays
Linked ELAVL4 to APP/tau processing in human neurons, with KO raising APP isoforms and phospho-tau and overexpression lowering Aβ42/40, situating it downstream of insulin receptor-FOXO1 signaling.
Evidence iPSC-derived neuron KO/overexpression/rescue, multi-omics, Aβ ELISA, p-tau assays
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 1991 | HuD contains three RNA recognition motif (RRM) domains and shows homology to Drosophila ELAV and Sex-lethal proteins, suggesting a role in neuron-specific RNA processing. | cDNA library screening, sequence analysis | Cell | Medium | 1655278 |
| 1996 | Purified HuD binds mRNAs containing AU-rich elements (AREs) with high affinity; only the first two RRM domains (RRM1 and RRM2) are essential for RNA binding, as shown by deletion analysis. | Protein purification, RNA binding assays, deletion mutagenesis | The Journal of biological chemistry | High | 8626712 |
| 2000 | All three RRM domains of HuD cooperate to bind AU-rich RNA: RRM1 is critical for affinity (deletion reduces Kd by ~100-fold), while RRM2 and RRM3 deletion increases both association and dissociation rates, suggesting a conformational change during binding that stabilizes the complex. | Surface plasmon resonance (BIACORE), equilibrium and kinetic binding assays, deletion analysis | Molecular and cellular biology | High | 10848602 |
| 2001 | Crystal structures of HuD RRM1 and RRM2 in complex with ARE RNA (c-fos ARE at 1.8 Å and TNFα ARE at 2.3 Å) reveal a consensus recognition sequence with preference for pyrimidine-rich sequences and a requirement for a central uracil in clustered AUUUA repeats; base recognition occurs via two pockets in conserved RNP motifs and C-terminal ends of RRM domains. | X-ray crystallography (crystal structures to 1.8 Å and 2.3 Å resolution) | Nature structural biology | High | 11175903 |
| 2001 | HuD overexpression increases the in vivo stability of MYCN mRNA by binding to AU-rich elements in the MYCN 3'-UTR, inhibiting decay mediated by cis-acting destabilizing elements. | Ectopic overexpression, in vivo mRNA decay assays, reporter constructs | The Journal of biological chemistry | Medium | 11711535 |
| 2001 | HuD overexpression in cortical neurons and retinoic acid-induced embryonic stem cells accelerates neurite outgrowth and increases GAP-43 mRNA levels, establishing HuD as a regulator of GAP-43 expression and neuronal differentiation. | HSV-1 vector overexpression, immunocytochemistry, in situ hybridization, quantitative RT-PCR | Experimental neurology | Medium | 11259113 |
| 2002 | HuD stabilizes GAP-43 mRNA through a mechanism dependent on poly(A) tail length: HuD delays mRNA degradation by decreasing deadenylation rate, and binds GAP-43 mRNAs with long poly(A) tails (A150) with ~10-fold higher affinity than short tails (A30). | PC12 cell overexpression, polysome-based in vitro mRNA decay assay, recombinant HuD addition, RNA binding affinity measurements | The Journal of biological chemistry | High | 12034726 |
| 2002 | HuD binds directly to AChE mRNA via AU-rich element in its 3'-UTR and regulates AChE mRNA abundance in neuronal cells; HuD overexpression stabilizes AChE transcripts while antisense HuD reduces them. | RNA gel shift, Northwestern blot, immunoprecipitation, stable HuD overexpression and antisense PC12 cells, reporter assays | The Journal of biological chemistry | Medium | 12468554 |
| 2002 | HuD binds three AU-rich sequences in the 3'-UTR of neuroserpin mRNA and stabilizes it; ectopic HuD expression in PC12 cells increases both neuroserpin mRNA and protein levels. | Gel shift, supershift, T1 RNase assays, RNA binding, overexpression in PC12 cells | Nucleic acids research | Medium | 12000840 |
| 2003 | HuD binds U-rich sequences with higher affinity than AU-rich sequences; all three RRM domains participate in binding AU-tracts as short as 13 residues; in vitro selection confirmed poly(U) preference for HuD. | RNA binding analysis with deletion mutants, in vitro SELEX selection with randomized RNAs, equilibrium binding assays | The Journal of biological chemistry | High | 12900401 |
| 1999 | Cytoplasmic localization of HuD is required for neuronal differentiation; the linker region between RBD2 and RBD3 contains a novel nuclear export signal (NES) required for nucleocytoplasmic shuttling and neurite-inducing activity in PC12 cells. | Deletion mutant analysis, neurite outgrowth assay in PC12 cells, dominant negative mutants, P19 cell differentiation assay | Genes to cells | Medium | 10620013 |
| 2003 | HuD and GAP-43 mRNA co-localize in cytoplasmic granules in growth cones of DRG neurons; GAP-43 mRNA-HuD granules are found in both central and peripheral domains of growth cones and co-localize with ribosomes; HuD granule distribution in growth cones depends on actin filaments but not microtubules. | Immunofluorescence, in situ hybridization, confocal microscopy, actin/microtubule disruption experiments | Experimental neurology | Medium | 12957493 |
| 2004 | TAP/NXF1, the primary mRNA export receptor, directly and specifically interacts with HuD (but not HuR); HuD forms a ternary complex with TAP and RNA, suggesting HuD acts as an adaptor for efficient ARE-mRNA nuclear export in neurons. | In vitro binding with recombinant proteins, co-immunoprecipitation, ternary complex assay | Biochemical and biophysical research communications | Medium | 15358174 |
| 2004 | HuD associates with tau mRNA in neurons; GST-HuD pulldown identified IMP-1 and G3BP-1 as proteins contained within the tau mRNA ribonucleoprotein complex; IMP-1 associates with HuD and G3BP-1 in an RNA-dependent manner. | GST-HuD fusion protein pulldown, RNA-dependent co-immunoprecipitation, Western blot | Journal of neurochemistry | Medium | 15086518 |
| 2004 | HuD is present in polysomal and cytosolic fractions of hippocampal neurons; it localizes to cytoplasmic granules in dendrites that co-stain with ribosomal marker Y10B; HuD protein levels increase in hippocampal hilus and CA3 after contextual fear conditioning. | Subcellular fractionation, immunoprecipitation, confocal microscopy, immunohistochemistry after behavioral paradigm | Neuroscience letters | Medium | 15519747 |
| 2006 | CARM1 (coactivator-associated arginine methyltransferase 1) directly methylates HuD in vitro and in vivo; methylation of HuD by CARM1 reduces its ability to stabilize p21(cip1/waf1) mRNA, thereby maintaining PC12 cells in a proliferative state; CARM1 knockdown elongates p21 mRNA half-life and promotes neuritogenesis. | In vitro methylation assay with purified proteins, siRNA knockdown, mRNA half-life assay, methylation-resistant HuD mutant overexpression | Molecular and cellular biology | High | 16508003 |
| 2006 | HuD overexpression in vivo in transgenic mice selectively increases GAP-43 mRNA stability (not pre-mRNA levels) in hippocampal dentate granule cells, amygdala, and cortex, confirmed by mRNA decay assays showing greater GAP-43 mRNA stability in brain extracts from HuD transgenic mice. | Transgenic mouse model, quantitative in situ hybridization comparing mRNA and pre-mRNA, mRNA decay assays | Journal of neurochemistry | High | 16405504 |
| 2007 | HuD directly binds AChE mRNA via its AU-rich 3'-UTR element in rat superior cervical ganglion neurons; after axotomy, HuD and its binding to AChE mRNA decrease, leading to reduced AChE mRNA stability; HSV-HuD infection maintains AChE and GAP-43 mRNA levels post-axotomy. | In vitro mRNA decay assays, RNA-protein complex analysis, HSV-mediated HuD overexpression in vivo, RT-PCR, immunoprecipitation | The Journal of neuroscience | High | 17234598 |
| 2008 | HuD shows activity-dependent dendritic localization following KCl stimulation in hippocampal neurons; HuD associates with mRNAs encoding neuritin, Homer1a, GAP-43, Neuroligins, Verge, and CAMKIIα; activity-dependent HuD expression requires NMDA receptor activation (reduced in NR1 knockout mice); HuD co-localizes with PABP and eIF4E in dendrites. | Immunofluorescence, RNA immunoprecipitation, KCl stimulation, NMDAR1 knockout mice analysis | RNA biology | Medium | 18769135 |
| 2009 | HuD stimulates cap-dependent translation requiring both a 3' poly(A) tail and 5' m7G cap; HuD directly interacts with eIF4A; both the eIF4A-interaction and poly(A)-binding activities of HuD are critical for its translational enhancer function and for HuD-induced neurite outgrowth in PC12 cells. | In vitro translation assays with HCV IRES controls, co-immunoprecipitation with eIF4A, HuD binding mutants, neurite outgrowth assay | Molecular cell | High | 20064466 |
| 2009 | Genome-wide identification of HuD targets by mRNP immunoprecipitation from brain and GST-HuD pulldown revealed novel recognition motifs including U-rich (motifs 2 and 3) and C-rich (motif 1) sequences; HuD targets are enriched in neuronal differentiation signaling, RBPs, translation factors, and actin-binding protein mRNAs. | mRNP immunoprecipitation from brain, GST pulldown, microarray, in vitro binding assays | Nucleic acids research | Medium | 19846595 |
| 2010 | SMN interacts with HuD in neurites of motor neurons; this interaction is mediated by the Tudor domain of SMN; patient-derived Tudor domain mutations causing severe SMA abrogate the interaction; CARM1 methylation of HuD reduces its interaction with p21 mRNA; HuD overexpression rescues SMA-like defects in a hypomorphic Smn knockdown cell line. | Co-immunoprecipitation, pull-down with purified proteins, site-directed mutagenesis (Tudor mutations), methylation assay, siRNA knockdown, rescue overexpression | Human molecular genetics | High | 21088113 |
| 2010 | miR-375 represses HuD expression through a specific, evolutionarily conserved site in the HuD 3' UTR by reducing both HuD mRNA stability and translation; miR-375 overexpression phenocopies HuD silencing in reducing dendrite density and levels of downstream targets (N-cadherin, PSD-95, RhoA, NCAM1, integrin α1); BDNF-induced neurite outgrowth increase is blocked by miR-375 and rescued by miR-375-refractory HuD. | Heterologous reporter assays, miRNA overexpression in hippocampus, HuD silencing, rescue with refractory HuD construct | Molecular and cellular biology | High | 20584986 |
| 2010 | Hu proteins (including HuD) promote inclusion of alternative exon 6 in their own pre-mRNA through conserved AU-rich sequences downstream of exon 6; this was confirmed by minigene reporter assays, Hu protein overexpression/knockdown, and in vitro splicing assays. | Minigene reporter assay, Hu protein overexpression and RNAi knockdown, in vitro splicing assay | Nucleic acids research | High | 20159993 |
| 2011 | SMN interacts with HuD in motor neuron axons in a Tudor domain-dependent manner; SMN knockdown in primary motor neurons reduces HuD protein and poly(A) mRNA levels in the axonal compartment; SMN and HuD co-transport in live motor neurons as shown by time-lapse microscopy and BiFC. | Bimolecular fluorescence complementation (BiFC), pulldown assays, immunofluorescence, cell transfection, time-lapse microscopy, SMN knockdown | The Journal of neuroscience | High | 21389246 |
| 2011 | SMN and HuD form a complex in spinal motor axons and both interact with cpg15 mRNA; SMN deficiency reduces cpg15 mRNA levels in neurons; cpg15 overexpression partially rescues the SMN-deficiency phenotype in zebrafish. | Mass spectrometry protein identification, co-immunoprecipitation, mRNA quantification, zebrafish rescue experiments | Proceedings of the National Academy of Sciences of the United States of America | High | 21652774 |
| 2012 | HuD is expressed in pancreatic β cells and binds a 22-nucleotide segment in the 5' UTR of Ins2 (preproinsulin) mRNA; HuD overexpression decreases Ins2 mRNA translation and insulin production without altering mRNA levels; HuD silencing enhances translation and insulin production; glucose treatment causes HuD to rapidly dissociate from Ins2 mRNA. | RNA immunoprecipitation, HuD overexpression/silencing, insulin measurement, HuD-KO and HuD-OE mice, glucose treatment assays | Molecular cell | High | 22387028 |
| 2013 | HuD interacts with the 3' UTRs of APP mRNA and BACE1 mRNA, increasing their half-lives; HuD also stabilizes lncRNA BACE1AS, which complements BACE1 mRNA and enhances BACE1 expression; HuD-overexpressing mice show higher APP, BACE1, BACE1AS, and Aβ levels in brain. | RNA immunoprecipitation, mRNA stability assays, HuD-overexpressing mouse model, Western blot | Cell reports | High | 24857657 |
| 2013 | mTORC1 inactivity promotes HuD binding to Kv1.1 mRNA and its translation; mTORC1 inhibition causes degradation of high-affinity HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA; miR-129 represses Kv1.1 mRNA translation when mTORC1 is active. | RNA immunoprecipitation, mTORC1 inhibition (rapamycin), miR-129 functional assays, HuD binding competition assays | The Journal of cell biology | Medium | 23836929 |
| 2013 | HuD interacts with a conserved AU-rich element specifically in the BDNF long 3'UTR, selectively stabilizing long 3'UTR BDNF mRNA isoforms in vitro and in vivo; HuD transgenic mice show increased BDNF long 3'UTR mRNA in dentate granule cells and elevated BDNF in mossy fiber terminals. | RNA immunoprecipitation, in vitro stability assays, HuD transgenic mouse model, in situ hybridization, Western blot | PloS one | High | 23383270 |
| 2013 | HuD associates with ATG5 mRNA 3'-UTR in pancreatic β cells; HuD modulates ATG5 mRNA translation (not mRNA levels); HuD promotes autophagosome formation via ATG5-dependent LC3 lipidation; HuD-null mice show lower ATG5 and LC3 in β cells. | RIP, biotin pulldown, HuD siRNA knockdown and overexpression, GFP-LC3 autophagosome assay, HuD-null mice | The Journal of biological chemistry | High | 24275661 |
| 2013 | HuD and ZBP1 form an RNA-dependent co-immunoprecipitable complex; a HuD-ZBP1 ribonucleoprotein complex binds the AU-rich regulatory element (ARE) in GAP-43 3'UTR and this ARE is necessary and sufficient for axonal localization of GAP-43 mRNA. | RNA immunoprecipitation, co-immunoprecipitation, reporter mRNA axonal localization assays, ARE deletion mutagenesis | Journal of neurochemistry | High | 23586486 |
| 2014 | Loss of HuD in early development results in defective dendritic overgrowth, impaired neuron specification in lower neocortical layers, hippocampal CA3 dendritogenesis defects, impaired Morris water maze performance, lower anxiety, and increased susceptibility to auditory-induced seizures. | HuD conditional knockout mice, histological analysis, dendrite morphometry, behavioral testing (Morris water maze, auditory seizure) | The Journal of neuroscience | High | 24599466 |
| 2015 | HuD promotes neuronal differentiation of NSCs by stabilizing SATB1 mRNA; SATB1 in turn transcriptionally activates HuD, forming a positive feedback loop; NeuroD1 is a downstream target of SATB1 in this pathway; SATB1 overexpression rescues neuronal differentiation defects from HuD deficiency. | HuD knockdown, SATB1 overexpression, mRNA stability assays, rescue experiments in adult SVZ NSCs | Proceedings of the National Academy of Sciences of the United States of America | High | 26305964 |
| 2015 | mTOR activity promotes branch-specific dendritic expression of CaMKIIα by preventing deadenylation of its mRNA; HuD overexpression preserves branch-specific CaMKIIα expression when mTOR is inhibited; deletion of HuD's third RRM (poly(A)-binding domain) eliminates branch-specific expression, indicating HuD captures CaMKIIα mRNA via poly(A) tail binding. | mTOR inhibition (rapamycin), HuD overexpression and RRM3 deletion mutants, dendritic branch-specific CaMKIIα imaging, poly(A) tail length assays | The Journal of biological chemistry | Medium | 25944900 |
| 2015 | HuD binds directly to sequences in the long Bdnf 3'UTR and co-localizes with Bdnf mRNA in dendrites; PKC activation (at T149 and/or T165 phosphorylation sites) promotes dendritic translation of long Bdnf 3'UTR mRNAs in a HuD-dependent manner. | In vivo RNA immunoprecipitation, co-localization by fluorescence microscopy, PKC activation, HuD phosphorylation site mutants, dendritic translation reporter assays | PloS one | Medium | 25692578 |
| 2015 | HuD and ZBP1 both bind the β-actin mRNA zipcode element in the 3' UTR, but with different requirements: HuD prefers U-rich sequence, while ZBP1 requires proper spatial organization of a stem-loop structure; their binding sites overlap. | Cell-free protein-RNA interaction assays, binding preference analysis with isolated cis-elements, mutagenesis | Nucleic acids research | Medium | 26152301 |
| 2016 | HuD binds the 3'UTR of Insig1 mRNA and promotes INSIG1 translation in pancreatic β cells; HuD downregulation reduces INSIG1, facilitating nuclear SREBP1c localization and transcriptional activation of lipogenic genes, increasing triglyceride production; HuD-null mice show lower INSIG1 in islets. | RIP, biotin pulldown, HuD siRNA and overexpression, SREBP1c nuclear localization assays, triglyceride measurement, HuD-null mice | Biochimica et biophysica acta | Medium | 26945853 |
| 2017 | SMN and HuD interact in zebrafish motoneurons in vivo; zebrafish HuD mutants show decreased motor axon branches, fewer dendrites, movement defects, and reduced Gap43 mRNA; HuD transgenic expression in motoneurons of SMN mutants rescues motoneuron defects, movement defects, and Gap43 mRNA levels. | Zebrafish SMN-HuD interaction (in vivo), zebrafish HuD loss-of-function mutants, transgenic rescue, mRNA quantification | The Journal of neuroscience | High | 29061699 |
| 2018 | HuD acts as a translation enhancer for mTORC1-responsive mRNAs (ribosomal proteins and translation factors) in a mTORC1-independent fashion; the predominant HuD RNA target is the small non-coding RNA Y3 (70% of HuD interaction signal), which acts as a molecular sponge dynamically limiting HuD recruitment to polysomes and its activity as a translation and neuronal differentiation enhancer. | CLIP-seq (nucleotide-resolution interactome mapping), polysome profiling, HuD overexpression/knockdown, translation efficiency assays, Y3 sponge functional assays | Molecular cell | High | 30029004 |
| 2019 | Mutant FUS (ALS-linked) shifts binding from introns to 3'UTRs; ELAVL4 mRNA is a target of mutant FUS, leading to increased ELAVL4 protein levels in mutant motor neurons; ELAVL4/mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties; upon oxidative stress they co-localize in stress granules; in FUS-ALS patient spinal cord, ELAVL4 is a component of FUS-positive cytoplasmic aggregates. | CLIP-seq (wild-type and mutant FUS), iPSC-derived motor neurons, co-immunoprecipitation, co-localization, stress granule assays, patient tissue analysis | Cell reports | High | 31242416 |
| 2019 | HuD promotes mitochondrial fusion in pancreatic β cells by binding to the 3'UTR of Mfn2 mRNA and positively regulating its expression; HuD knockdown increases mitochondrial fragmentation and reduces mitochondrial membrane potential and ATP production; Mfn2 overexpression rescues HuD-knockdown-induced mitochondrial dysfunction. | RIP, HuD knockdown (shRNA), Mfn2 overexpression rescue, mitochondrial morphology imaging, membrane potential and ATP assays, HuD KO and db/db mice | Cell death and differentiation | High | 31659282 |
| 2020 | Translation of distinct Elavl4 mRNA isoforms in radial glia progenitors and early neurons is regulated by alternative 5' UTRs; 5'UTR-driven Elavl4 isoform-specific translation depends on upstream regulation by another RBP, Celf1; Celf1 regulation of Elavl4 translation controls glutamatergic neuron development. | RNA-seq of neocortical polysomes, reporter assays for 5'UTR activity, Celf1 manipulation, neuronal differentiation analysis | Nature communications | Medium | 32245946 |
| 2020 | HuD specifically binds SOD1 mRNA ARE motifs and promotes its stabilization; oxidative stress increases HuD binding to SOD1 mRNA and causes alternative polyadenylation (APA) site shift to a longer variant bearing HuD binding sites; HuD siRNA knockdown prevents SOD1 upregulation during H2O2 treatment; in sALS motor cortex, HuD and SOD1 mRNAs and proteins are co-elevated with increased HuD-SOD1 mRNA binding. | In vitro binding assays, mRNA decay assays, HuD overexpression and dominant negative, siRNA knockdown, H2O2 oxidative stress, APA analysis, RIP from patient tissues | Neurobiology of disease | Medium | 33271327 |
| 2021 | ALS-causing mutant FUS leads to upregulation of HuD protein through competition with FMRP for binding to the HuD mRNA 3'UTR; increased HuD levels overly stabilize target transcripts NRN1 and GAP43, causing increased axon branching and growth that can be rescued by dampening NRN1 levels. | iPSC-derived motor neurons and mouse models with FUS mutations, RIP, HuD and FMRP binding competition assays, axon growth measurements, NRN1 rescue experiments | Communications biology | High | 34471224 |
| 2022 | ELAVL4 knockout in human iPSC-derived neurons increases APP isoform levels and intracellular phosphorylated tau; ELAVL4 overexpression reduces extracellular Aβ42/40 ratio; rescue experiments confirm ELAVL4 modulates APP and tau processing; pathway analysis suggests ELAVL4 expression is regulated by insulin receptor-FOXO1 signaling in neurons. | ELAVL4 KO iPSC-derived neurons, overexpression, rescue experiments, transcriptomic and proteomic analysis, APP isoform quantification, Aβ ELISA, p-tau immunoassay | Progress in neurobiology | Medium | 35843356 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 1991 | HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. | Cell | 538 | 1655278 |
| 2001 | Structural basis for recognition of AU-rich element RNA by the HuD protein. | Nature structural biology | 218 | 11175903 |
| 2005 | The RNA-binding protein HuD regulates neuronal cell identity and maturation. | Proceedings of the National Academy of Sciences of the United States of America | 183 | 15764704 |
| 2011 | The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. | The Journal of neuroscience : the official journal of the Society for Neuroscience | 178 | 21389246 |
| 2011 | Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. | Proceedings of the National Academy of Sciences of the United States of America | 171 | 21652774 |
| 2004 | Increase of the RNA-binding protein HuD and posttranscriptional up-regulation of the GAP-43 gene during spatial memory. | Proceedings of the National Academy of Sciences of the United States of America | 158 | 14745023 |
| 2002 | Role of HuD and other RNA-binding proteins in neural development and plasticity. | Journal of neuroscience research | 158 | 11948657 |
| 1996 | Purification and properties of HuD, a neuronal RNA-binding protein. | The Journal of biological chemistry | 155 | 8626712 |
| 2004 | The insulin-like growth factor mRNA binding-protein IMP-1 and the Ras-regulatory protein G3BP associate with tau mRNA and HuD protein in differentiated P19 neuronal cells. | Journal of neurochemistry | 133 | 15086518 |
| 1995 | Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. | Neurology | 130 | 7477985 |
| 2021 | ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. | Cell | 125 | 34314701 |
| 2010 | HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. | Human molecular genetics | 115 | 21088113 |
| 2010 | miR-375 inhibits differentiation of neurites by lowering HuD levels. | Molecular and cellular biology | 109 | 20584986 |
| 2006 | CARM1 regulates proliferation of PC12 cells by methylating HuD. | Molecular and cellular biology | 108 | 16508003 |
| 2013 | Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction. | RNA (New York, N.Y.) | 104 | 23861535 |
| 1999 | Cytoplasmic localization is required for the mammalian ELAV-like protein HuD to induce neuronal differentiation. | Genes to cells : devoted to molecular & cellular mechanisms | 100 | 10620013 |
| 2013 | Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1. | The Journal of cell biology | 99 | 23836929 |
| 2014 | HuD regulates coding and noncoding RNA to induce APP→Aβ processing. | Cell reports | 98 | 24857657 |
| 2003 | Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility. | Gastroenterology | 97 | 12851872 |
| 2009 | Novel recognition motifs and biological functions of the RNA-binding protein HuD revealed by genome-wide identification of its targets. | Nucleic acids research | 96 | 19846595 |
| 2006 | The RNA-binding protein HuD: a regulator of neuronal differentiation, maintenance and plasticity. | BioEssays : news and reviews in molecular, cellular and developmental biology | 94 | 16927307 |
| 2000 | HuD RNA recognition motifs play distinct roles in the formation of a stable complex with AU-rich RNA. | Molecular and cellular biology | 94 | 10848602 |
| 2012 | RNA-binding protein HuD controls insulin translation. | Molecular cell | 87 | 22387028 |
| 2009 | The ELAV protein HuD stimulates cap-dependent translation in a Poly(A)- and eIF4A-dependent manner. | Molecular cell | 87 | 20064466 |
| 2002 | Poly(A) tail length-dependent stabilization of GAP-43 mRNA by the RNA-binding protein HuD. | The Journal of biological chemistry | 85 | 12034726 |
| 2001 | Overexpression of HuD accelerates neurite outgrowth and increases GAP-43 mRNA expression in cortical neurons and retinoic acid-induced embryonic stem cells in vitro. | Experimental neurology | 83 | 11259113 |
| 2009 | Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells. | The Journal of clinical investigation | 79 | 19509467 |
| 2004 | GAP-43 mRNA in growth cones is associated with HuD and ribosomes. | Journal of neurobiology | 73 | 15389607 |
| 2013 | A HuD-ZBP1 ribonucleoprotein complex localizes GAP-43 mRNA into axons through its 3' untranslated region AU-rich regulatory element. | Journal of neurochemistry | 72 | 23586486 |
| 2007 | Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing. | The EMBO journal | 70 | 17332745 |
| 1998 | DNA vaccination with HuD inhibits growth of a neuroblastoma in mice. | Clinical cancer research : an official journal of the American Association for Cancer Research | 67 | 9829748 |
| 2005 | Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease. | Human genetics | 60 | 15827745 |
| 2004 | Dendritic localization of the RNA-binding protein HuD in hippocampal neurons: association with polysomes and upregulation during contextual learning. | Neuroscience letters | 60 | 15519747 |
| 2014 | Prenatal deletion of the RNA-binding protein HuD disrupts postnatal cortical circuit maturation and behavior. | The Journal of neuroscience : the official journal of the Society for Neuroscience | 57 | 24599466 |
| 2003 | Increased expression and localization of the RNA-binding protein HuD and GAP-43 mRNA to cytoplasmic granules in DRG neurons during nerve regeneration. | Experimental neurology | 57 | 12957493 |
| 2006 | Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD. | Neurobiology of learning and memory | 55 | 17185008 |
| 2006 | In vivo post-transcriptional regulation of GAP-43 mRNA by overexpression of the RNA-binding protein HuD. | Journal of neurochemistry | 54 | 16405504 |
| 2005 | T cell response to Hu-D peptides in patients with anti-Hu syndrome. | Journal of neuro-oncology | 53 | 15735910 |
| 2002 | Post-transcriptional regulation of acetylcholinesterase mRNAs in nerve growth factor-treated PC12 cells by the RNA-binding protein HuD. | The Journal of biological chemistry | 53 | 12468554 |
| 2019 | Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis. | Cell reports | 52 | 31242416 |
| 2001 | HuD, a neuronal-specific RNA-binding protein, increases the in vivo stability of MYCN RNA. | The Journal of biological chemistry | 52 | 11711535 |
| 2015 | Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis. | Proceedings of the National Academy of Sciences of the United States of America | 50 | 26305964 |
| 2013 | HuD promotes BDNF expression in brain neurons via selective stabilization of the BDNF long 3'UTR mRNA. | PloS one | 50 | 23383270 |
| 1994 | Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines. | Cancer research | 50 | 8069866 |
| 2008 | Activity-dependent expression of RNA binding protein HuD and its association with mRNAs in neurons. | RNA biology | 48 | 18769135 |
| 2003 | Characterization of the interaction between neuronal RNA-binding protein HuD and AU-rich RNA. | The Journal of biological chemistry | 48 | 12900401 |
| 2018 | HuD Is a Neural Translation Enhancer Acting on mTORC1-Responsive Genes and Counteracted by the Y3 Small Non-coding RNA. | Molecular cell | 47 | 30029004 |
| 2020 | Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development. | Nature communications | 46 | 32245946 |
| 1999 | HuD, a neuronal-specific RNA-binding protein, is a putative regulator of N-myc pre-mRNA processing/stability in malignant human neuroblasts. | Oncogene | 45 | 10348344 |
| 2002 | HuD binds to three AU-rich sequences in the 3'-UTR of neuroserpin mRNA and promotes the accumulation of neuroserpin mRNA and protein. | Nucleic acids research | 44 | 12000840 |
| 2000 | RNA-binding analyses of HuC and HuD with the VEGF and c-myc 3'-untranslated regions using a novel ELISA-based assay. | Nucleic acids research | 43 | 10710437 |
| 2013 | Role of HuD in nervous system function and pathology. | Frontiers in bioscience (Scholar edition) | 42 | 23277068 |
| 2003 | The 3'-UTR of the mRNA coding for the major protein kinase C substrate MARCKS contains a novel CU-rich element interacting with the mRNA stabilizing factors HuD and HuR. | European journal of biochemistry | 41 | 12605686 |
| 2010 | Promotion of exon 6 inclusion in HuD pre-mRNA by Hu protein family members. | Nucleic acids research | 40 | 20159993 |
| 2017 | HuD and the Survival Motor Neuron Protein Interact in Motoneurons and Are Essential for Motoneuron Development, Function, and mRNA Regulation. | The Journal of neuroscience : the official journal of the Society for Neuroscience | 39 | 29061699 |
| 2015 | Mammalian Target of Rapamycin (mTOR) Tagging Promotes Dendritic Branch Variability through the Capture of Ca2+/Calmodulin-dependent Protein Kinase II α (CaMKIIα) mRNAs by the RNA-binding Protein HuD. | The Journal of biological chemistry | 39 | 25944900 |
| 2021 | RNA-Binding Protein HuD as a Versatile Factor in Neuronal and Non-Neuronal Systems. | Biology | 37 | 33922479 |
| 2013 | The RNA-binding protein HuD regulates autophagosome formation in pancreatic β cells by promoting autophagy-related gene 5 expression. | The Journal of biological chemistry | 36 | 24275661 |
| 2007 | The RNA-binding protein HuD binds acetylcholinesterase mRNA in neurons and regulates its expression after axotomy. | The Journal of neuroscience : the official journal of the Society for Neuroscience | 36 | 17234598 |
| 2020 | HuD Binds to and Regulates Circular RNAs Derived From Neuronal Development- and Synaptic Plasticity-Associated Genes. | Frontiers in genetics | 35 | 32849796 |
| 2017 | HuD-mediated distinct BDNF regulatory pathways promote regeneration after nerve injury. | Brain research | 35 | 28111162 |
| 2008 | Replication of association between ELAVL4 and Parkinson disease: the GenePD study. | Human genetics | 35 | 18587682 |
| 1998 | Expression of mRNA for the elav-like neural-specific RNA binding protein, HuD, during nervous system development. | Brain research. Developmental brain research | 35 | 9729424 |
| 2013 | Neuroserpin up-regulation in the Alzheimer's disease brain is associated with elevated thyroid hormone receptor-β1 and HuD expression. | Neurochemistry international | 34 | 24036060 |
| 2007 | Dynamic association with polysomes during P19 neuronal differentiation and an untranslated-region-dependent translation regulation of the tau mRNA by the tau mRNA-associated proteins IMP1, HuD, and G3BP1. | Journal of neuroscience research | 34 | 17086542 |
| 2012 | Identification of continuous epitopes of HuD antibodies related to paraneoplastic diseases/small cell lung cancer. | Journal of neuroimmunology | 33 | 22264992 |
| 2007 | Coordinated expression of HuD and GAP-43 in hippocampal dentate granule cells during developmental and adult plasticity. | Neurochemical research | 33 | 17577668 |
| 2014 | PKC-mediated HuD-GAP43 pathway activation in a mouse model of antiretroviral painful neuropathy. | Pharmacological research | 31 | 24565699 |
| 2000 | Demonstration of anti-HuD specific oligoclonal bands in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes. Qualitative evidence of anti-HuD specific IgG-synthesis in the central nervous system. | Journal of neuroimmunology | 31 | 11063845 |
| 2021 | ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity. | Communications biology | 30 | 34471224 |
| 2019 | RNA binding protein HuD contributes to β-cell dysfunction by impairing mitochondria dynamics. | Cell death and differentiation | 30 | 31659282 |
| 1998 | Selection of recombinant anti-HuD Fab fragments from a phage display antibody library of a lung cancer patient with paraneoplastic encephalomyelitis. | Journal of neuroimmunology | 29 | 9585817 |
| 1998 | Expression of HuD protein is essential for initial phase of neuronal differentiation in rat pheochromocytoma PC12 cells. | Biochemical and biophysical research communications | 28 | 9514914 |
| 1994 | Tissue-specific expression of the gene encoding a mouse RNA binding protein homologous to human HuD antigen. | DNA research : an international journal for rapid publication of reports on genes and genomes | 28 | 8535975 |
| 2015 | Different motif requirements for the localization zipcode element of β-actin mRNA binding by HuD and ZBP1. | Nucleic acids research | 27 | 26152301 |
| 2004 | TAP/NXF1, the primary mRNA export receptor, specifically interacts with a neuronal RNA-binding protein HuD. | Biochemical and biophysical research communications | 26 | 15358174 |
| 1997 | HuD, a neuronal-specific RNA-binding protein, is a potential regulator of MYCN expression in human neuroblastoma cells. | European journal of cancer (Oxford, England : 1990) | 26 | 9516855 |
| 2010 | Molecular analysis of the HuD gene in neuroendocrine lung cancers. | Lung cancer (Amsterdam, Netherlands) | 25 | 19410329 |
| 2005 | Potential application of ELAVL4 real-time quantitative reverse transcription-PCR for detection of disseminated neuroblastoma cells. | Clinical chemistry | 25 | 16384890 |
| 2020 | HuD regulates SOD1 expression during oxidative stress in differentiated neuroblastoma cells and sporadic ALS motor cortex. | Neurobiology of disease | 24 | 33271327 |
| 2011 | Increased expression of axogenesis-related genes and mossy fibre length in dentate granule cells from adult HuD overexpressor mice. | ASN neuro | 24 | 22004431 |
| 2014 | The RNA-binding protein HuD promotes spinal GAP43 overexpression in antiretroviral-induced neuropathy. | Experimental neurology | 23 | 24861443 |
| 2003 | Neuronal HuD gene encoding a mRNA stability regulator is transcriptionally repressed by thyroid hormone. | Journal of neurochemistry | 23 | 12859688 |
| 1994 | Mapping of the gene coding for a paraneoplastic encephalomyelitis antigen (HuD) to human chromosome site 1p34. | Cytogenetics and cell genetics | 23 | 8222755 |
| 2022 | RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons. | Progress in neurobiology | 22 | 35843356 |
| 2016 | RNA-binding protein HuD reduces triglyceride production in pancreatic β cells by enhancing the expression of insulin-induced gene 1. | Biochimica et biophysica acta | 22 | 26945853 |
| 2015 | HuD interacts with Bdnf mRNA and is essential for activity-induced BDNF synthesis in dendrites. | PloS one | 22 | 25692578 |
| 2014 | Intratumoral anti-HuD immunotoxin therapy for small cell lung cancer and neuroblastoma. | Journal of hematology & oncology | 22 | 25523825 |
| 2003 | Peptides derived from the onconeural HuD protein can elicit cytotoxic responses in HHD mouse and human. | Journal of neuroimmunology | 22 | 14512168 |
| 1996 | The RNA binding protein HuD: rat cDNA and analysis of the alternative spliced mRNA in neuronal differentiating cell lines P19 and PC12. | Brain research. Molecular brain research | 22 | 8717365 |
| 2017 | Axonal localization of neuritin/CPG15 mRNA is limited by competition for HuD binding. | Journal of cell science | 21 | 28871047 |
| 2014 | PKCε promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced Aβ degradation in brain neurons. | PloS one | 21 | 24848988 |
| 1999 | Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome. | Journal of neurology, neurosurgery, and psychiatry | 21 | 9886463 |
| 2009 | Tolerance to the neuron-specific paraneoplastic HuD antigen. | PloS one | 20 | 19492067 |
| 2008 | Alterations in mossy fiber physiology and GAP-43 expression and function in transgenic mice overexpressing HuD. | Hippocampus | 20 | 18493953 |
| 1999 | DNA vaccination against HuD antigen elicits antitumor activity in a small-cell lung cancer murine model. | American journal of respiratory cell and molecular biology | 20 | 10385591 |
| 2022 | Emerging Roles for the RNA-Binding Protein HuD (ELAVL4) in Nervous System Diseases. | International journal of molecular sciences | 19 | 36498933 |
| 2002 | Ectopic expression of Drosophila ELAV and human HuD in Drosophila wing disc cells reveals functional distinctions and similarities. | Journal of cell science | 19 | 12006625 |
| 1997 | Differential expression of the neuroendocrine genes Hel-N1 and HuD in small-cell lung carcinoma: evidence for down-regulation of HuD in the variant phenotype. | International journal of cancer | 19 | 9291425 |
| 1998 | Gene organization and chromosome location of the neural-specific RNA binding protein Elavl4. | Gene | 18 | 9524251 |
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