Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction

Hu binding sites are mostly located in 3′ UTRs of mRNAs, with a significant portion in introns and relatively few in 5′ UTRs.

“These studies also found that Hu binding sites were mostly located in 3′ UTRs of mRNAs, with a significant portion in introns and relatively few in 5′ UTRs.”

• cites Lebedeva et al. 2011 sourceSupported
• cites Mukherjee et al. 2011 sourceDisputed

  The Results section (HuR-RNA interactions and RNA Recognition Element, Figure 2A; page not available) reports 83,141 intronic binding-site clusters versus 22,353 in 3′ UTRs. Thus, although substantial 3′ UTR binding is reported, the claim that most sites are in 3′ UTRs is contrary to this paper's counts. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Uren et al. 2011 sourcePartly supported

  The Results and Discussion text and Figure 1 caption report a large proportion of HuR iCLIP sites in 3′ UTRs and many in introns. Our copy does not establish that most sites are in 3′ UTRs or explicitly compare the number in 5′ UTRs, so those parts of the claim are not fully supported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In the developing mouse and rat cerebral cortex, HuD mRNA is present in proliferating neuronal stem/progenitor cells in the ventricular zone, neuroblasts migrating in the intermediate zones, and terminally differentiating neurons in the cortical plate.

“In the developing mouse and rat cerebral cortex, HuD mRNA is present in proliferating neuronal stem/progenitor cells in the ventricular zone, neuroblasts migrating in the intermediate zones, and terminally differentiating neurons in the cortical plate (Okano and Darnell 1997; Clayton et al. 1998).”

• cites Okano and Darnell 1997 sourceDisputed

  The Figure 7 caption and “Hierarchies of mHu mRNA expression in developing neurons” section report mHuD mRNA in the intermediate zone and at diminishing levels in the cortical plate, but say it is very weak or absent in differentiated neurons. The section says mHuD mRNA is first evident in intermediate-zone neurons, contrary to the claim of its presence in proliferating ventricular-zone cells. These observations concern mouse cortex; the passages do not report rat cortex. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Clayton et al. 1998 sourceNot checked — no full text of the source

These interactions require the presence of RNA, since HuR and AUF1 were shown to simultaneously or competitively bind onto exclusive or common cis-acting elements in the 3′ UTRs of p21cip1/waf1, Cyclin D, TNFα, and β2-adrenergic receptor mRNAs.

“Moreover, these interactions require the presence of RNA, since HuR and AUF1 were shown to simultaneously or competitively bind onto exclusive or common, respectively, cis-acting elements in the 3′ UTRs of p21cip1/waf1, Cyclin D, TNFα, and β2-adrenergic receptor mRNAs (Lal et al. 2004; David et al. 2007).”

• cites Lal et al. 2004 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites David et al. 2007 sourceDisputed

  Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In the adult mouse and rodent nervous system, HuD mRNA expression is mostly restricted to specific neuronal populations, including large pyramidal-like neurons in layer V of the neocortex and cerebellar cortex (Purkinje cells), the four Cornu Amonis (CA1-4) regions of the hippocampus, dorsal root ganglia, motor neurons in the spinal cord, mitral cells in the olfactory bulb, ganglion and internal P

“In the adult mouse and rodent nervous system, expression of HuD mRNA is mostly restricted to specific neuronal populations, including large pyramidal-like neurons in layer V of the neocortex and cerebellar cortex (Purkinje cells), the four Cornu Amonis (CA1-4) regions of the hippocampus, dorsal root ganglia, and motor neurons in the spinal cord, mitral cells in the olfactory bulb, ganglion and int”

• cites Okano and Darnell 1997 sourcePartly supported

  The ‘mHu mRNA expression in adult brain’ section (page unavailable) reports HuD mRNA in layer 5 neocortical neurons, hippocampal pyramidal neurons, dorsal root ganglia, and olfactory mitral cells. But the paper explicitly says HuD is absent from Purkinje cells; it also does not identify spinal motor neurons as HuD-expressing, saying instead that spinal-cord neurons predominantly express HuC. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Clayton et al. 1998 sourceNot checked — no full text of the source
• cites D’Autreaux et al. 2011 sourcePartly supported

  The Methods and Results (page unavailable) describe HuD as neuron-specific and report its expression in the mouse enteric nervous system. They do not describe the claimed restriction of HuD mRNA to the listed brain regions, dorsal root ganglia, or spinal motor neurons. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Quantitative RT-PCR and Western blot analysis revealed relatively minor, although significant, HuD mRNA and protein levels in several nonneuronal tissues including lung, testes, liver, pituitary gland, pancreatic β cells, and fiber cells of the lens.

“In addition to being expressed in various neuronal subpopulations in the CNS and PNS, quantitative RT-PCR and Western blot analysis revealed relatively minor, although significant, HuD mRNA and protein levels in several nonneuronal tissues including lung, testes, liver, pituitary gland, pancreatic β cells, and fiber cells of the lens (Abdelmohsen et al. 2010; Bitel et al. 2010; Lee et al. 2012).”

• cites Abdelmohsen et al. 2010 sourceNot checked — no full text of the source
• cites Bitel et al. 2010Not checked — no full text of the source
• cites Lee et al. 2012 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Binding of Hu protein to the poly(A) tail depends on tail length; the longer the poly(A) tail, the higher the affinity of Hu protein binding to its target mRNA.

“Binding to the poly(A) tail seems to depend on the tail length, since results from in vitro binding assays demonstrated that the longer the poly(A) tail, the higher the affinity of Hu protein binding to its target mRNA (Beckel-Mitchener et al. 2002).”

• cites Beckel-Mitchener et al. 2002 sourcePartly supported

  The section “HuD Binds with Higher Affinity to GAP-43 Molecules with Long Poly(A) Tails” reports an eightfold higher affinity for GAP-43 mRNA with an A150 tail than with an A30 tail in an in vitro binding assay. The Discussion clarifies that the assay measured HuD binding to a site in the 3′-UTR as a function of tail length, not direct binding to the poly(A) tail; direct tail binding is presented as consistent with the data, not demonstrated by that assay. Page numbers were not supplied in the passages. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

HuD is one of the earliest markers of the neuronal phenotype.

“Converging findings suggest that HuD is one of the earliest markers of the neuronal phenotype (Good 1995; Okano and Darnell 1997; Wakamatsu and Weston 1997; Hambardzumyan et al. 2009).”

• Also stated in: § CONCLUSION AND PERSPECTIVE · plain

  “The Hu member HuD is one of the earliest markers of the neuronal phenotype and is broadly expressed in the mature nervous system.”

• cites Good 1995 sourceNot checked — no full text of the source
• cites Okano and Darnell 1997 sourcePartly supported

  The Abstract reports mHuD expression in migrating neurons during early cortical development, supporting its association with an early neuronal stage. But the sections “Hierarchies of mHu mRNA expression in developing neurons” and “The role of Hu proteins in neural development” identify mHuB, not mHuD, as expressed in the earliest postmitotic neurons. The paper therefore does not establish HuD as one of the earliest markers of the neuronal phenotype. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Wakamatsu and Weston 1997 sourceNot checked — no full text of the source

The spatial expression of HuD mRNA is partially unique compared to HuB and HuC.

“In situ hybridization analyses of nELAV expression in the mouse brain at day 14 of embryogenesis (E14) have revealed that the spatial expression of HuD mRNA is also partially unique compared to HuB and HuC (Okano and Darnell 1997), thus further supporting the notion that HuD is not completely functionally redundant.”

• cites Okano and Darnell 1997 sourceSupported

High-throughput analyses of HuR and nELAV target mRNAs demonstrate that all four Hu proteins preferentially bind U-rich sequences interspersed with Gs or As.

“Recent high-throughput analyses, using variations of cross-linking and immunoprecipitation (CLIP) such as Photoactivatable-Ribonucleoside-Enhanced CLIP (PAR-CLIP) and individual-nucleotide resolution CLIP (iCLIP), of HuR and nELAV target mRNAs corroborate these findings by demonstrating that all four Hu proteins preferentially bind U-rich sequences interspersed with Gs or As (Lebedeva et al. 2011;”

• cites Lebedeva et al. 2011 sourcePartly supported

  The section “PAR-CLIP reproducibly recovers in vitro HuR motifs” reports abundant HuR-binding motifs that are U-rich, including sequences containing A or G. The Introduction says HuB, HuC and HuD bind U-rich elements, but this paper’s high-throughput motif analysis is of HuR; it does not demonstrate the stated G- or A-interspersed preference for all four Hu proteins. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Mukherjee et al. 2011 sourcePartly supported

  The Results section ('HuR-RNA interactions and RNA Recognition Element'; page unavailable) reports a PAR-CLIP analysis of HuR and identifies U-rich motifs interrupted by A or C. The Introduction describes uridine stretches separated by adenosines or, less commonly, other bases. This paper does not demonstrate the stated preference for Gs or As across all four Hu proteins; its high-throughput analysis examines HuR. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Uren et al. 2011 sourcePartly supported

  The Results and Discussion section reports iCLIP evidence that HuR binding sites are enriched for U-rich sequences. It does not report binding preferences for HuB, HuC, or HuD, or establish that Gs or As are interspersed in the preferred sequences. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

nELAVs preferentially bind introns surrounding cassette exons, especially near exon/intron splice junctions.

“The same report also used genome wide analysis to map the binding sites in nELAV targeted pre-mRNAs and revealed that these proteins preferentially bind introns surrounding cassette exons, especially near exon/intron splice junctions (Ince-Dunn et al. 2012).”

• cites Ince-Dunn et al. 2012 sourceSupported

Destabilizing RBPs may promote deadenylation by blocking poly(A) binding protein (PABP) binding and/or recruiting decapping, deadenylation, and exosome components.

“Once bound to a target mRNA, destabilizing RBPs may promote deadenylation through a variety of manners such as blocking poly(A) binding protein (PABP) binding and/or recruitment of decapping, deadenylation, and exosome components (Wu and Brewer 2012).”

• cites Wu and Brewer 2012 sourcePartly supported

  Section 4.1 says AUF1 may prevent PABP from binding poly(A), allowing deadenylases access, and that KSRP, TTP, and BRF1 interact with deadenylation, decapping, and exosome factors. It describes those recruited factors as promoting mRNA degradation overall, however, and places exosome-mediated degradation after deadenylation; it does not say that recruiting decapping or exosome components promotes deadenylation itself. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

All three RRMs are necessary for Hu proteins to perform alternative polyadenylation.

“Truncation of the mouse HuB protein revealed that all three RRMs are necessary for Hu proteins to perform this function (Zhu et al. 2006).”

• cites Zhu et al. 2006 sourcePartly supported

  The Results report that Hu proteins regulate alternative processing of calcitonin/CGRP RNA and that a mouse HuC construct containing RRM3 and the hinge domain disrupted CGRP production, whereas an RRM1–RRM2 construct did not significantly affect exon inclusion. These experiments do not establish that all three RRMs are necessary for alternative polyadenylation, and the tested truncations were of mouse HuC, not mouse HuB. The cited copy provides no page numbers for these passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Both the Drosophila ELAV and the mammalian Hu proteins control alternative polyadenylation specifically in neurons.

“In addition to alternative splicing, both the Drosophila ELAV and the mammalian Hu proteins were demonstrated to control alternative polyadenylation specifically in neurons (Soller and White 2003).”

• cites Soller and White 2003 sourcePartly supported

  The Discussion reports that Drosophila ELAV inhibits 3′-end formation at an intronic polyadenylation site, promoting neuronal splicing of ewg. The paper does not demonstrate the same control by mammalian Hu proteins; its introductory passage instead describes their previously assigned functions as cytoplasmic RNA processing. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

By blocking HDAC2 activity, histones surrounding specific exons remain hyperacetylated, resulting in an increased RNAPII transcription rate and decreased exon inclusion at these genomic loci.

“In vitro transcription elongation assays showed that, by blocking HDAC2 activity, histones surrounding specific exons remained hyperacetylated, which resulted in an increased RNAPII transcription rate and decreased exon inclusion at these genomic loci.”

• cites Zhou et al. 2011 sourcePartly supported

  The Discussion (page unavailable) proposes that Hu proteins inhibit HDAC2, sustaining local histone hyperacetylation and increasing RNAPII elongation; the elongation-rate Results report decreased Nf1 exon 23a inclusion with HuC expression. But the claim misidentifies the evidence as in vitro transcription elongation assays: the in vitro assay measured HDAC2 activity, while elongation was measured in cells. The full causal chain is presented as a proposed mechanism, not as the result of one assay. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

All four Hu members promote inclusion of HuD exon 6 by binding to two ARE sequences in the downstream intron.

“For instance, all four Hu members were shown to promote inclusion of HuD exon 6 by binding to two ARE sequences in the downstream intron (Wang et al. 2010).”

• cites Wang et al. 2010 sourceSupported

GAP-43 mRNA houses a class III ARE in its 3′ UTR.

“Among all of the HuD-regulated mRNAs, the most prominent is the GAP-43 mRNA, which houses a class III ARE in its 3′ UTR (Chung et al. 1997; Tsai et al. 1997).”

• cites Chung et al. 1997 sourcePartly supported

  The paper describes a conserved U-rich element in the GAP-43 mRNA 3′ UTR and maps a 26-nucleotide HuD-binding site there (Abstract; HuD binding-site section, page unavailable). Our copy does not identify that element as a class III ARE, so the specific classification is not established by this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Tsai et al. 1997 sourcePartly supported

  The Discussion (page not available) says the GAP-43 3′ UTR contains sequences resembling AU-rich elements, and the section on cis-acting elements identifies a U-rich instability determinant there. Our copy does not classify that element as a class III ARE, so it supports the location and general type of element but not the specific classification. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

All four Hu proteins differentially regulate alternative polyadenylation of HuR in neurons.

“Moreover, all four Hu proteins were recently demonstrated to differentially regulate alternative polyadenylation of HuR in neurons (Mansfield and Keene 2011; also see Dai et al. 2012).”

• cites Mansfield and Keene 2011 sourcePartly supported

  The Introduction (page unavailable) says all four Hu proteins can drive alternative polyadenylation of HuR mRNA to produce a neuron-specific isoform. However, the regulation experiments were conducted in HEK293T cells, not neurons, and the Discussion describes the proteins’ differing efficiencies as an observation that remains to be rigorously tested. The source therefore does not establish that all four differentially regulate HuR polyadenylation in neurons. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Dai et al. 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Hu proteins interact with RNA polymerase II and histone deacetylase 2 (HDAC2) to regulate alternative splicing.

“In addition to binding intronic sequences, co-IP assays revealed that Hu proteins interact with RNA polymerase II and histone deacetylase 2 (HDAC2) to regulate alternative splicing (Zhou et al. 2011).”

• cites Zhou et al. 2011 sourceSupported

HuD mediates alternative splicing of the Ikaros gene, possibly by suppressing exon 4 inclusion.

“Furthermore, overexpression and down-regulation of HuD in T-cell lines demonstrated that it mediates alternative splicing of the Ikaros gene, possibly by suppressing exon 4 inclusion (Bellavia et al. 2007; Hinman and Lou 2008).”

• cites Bellavia et al. 2007 sourcePartly supported

  The section on HuD-dependent IK variants and Figure 6 report that HuD overexpression in T-cell lines increased short Ikaros dominant-negative isoforms, while HuD knockdown prevented Notch3-induced changes in those isoforms. The paper also identifies an exon-4-lacking Ikaros isoform, but does not establish that HuD specifically suppresses exon 4 inclusion; it leaves open effects on splicing and/or RNA stability. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Hinman and Lou 2008 sourceSupported

nELAVs compete with TIA-1/TIAR RBPs for a U-rich intronic sequence in the calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA to block inclusion of exon 4, thereby promoting expression of the neuron-specific CGRP isoform in neurons.

“Using various complementary methods, such as REMSA and UV cross-linking/IP assays, one report demonstrated that nELAVs compete with TIA-1/TIAR RBPs for a U-rich intronic sequence in the calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA to block inclusion of exon 4. Through this mechanism, nELAVs promote expression of the neuron-specific CGRP isoform in neurons (Zhu et al. 2006).”

• cites Zhu et al. 2006 sourceSupported

The linker region and RRM3 are necessary for nELAV regulation of alternative splicing.

“Experiments with HuB and HuC deletion mutants indicated that the linker region and RRM3 are necessary for nELAV regulation of alternative splicing (Zhu et al. 2008; Zhou et al. 2011).”

• cites Zhu et al. 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhou et al. 2011 sourcePartly supported

  The section ‘Hu Proteins Associate with Transcriptionally Active RNAPII in Neuronal’ reports that deleting RRM3 or the hinge domain reduced HuC’s interaction with RNAPII. It does not establish that these regions are necessary for nELAV regulation of alternative splicing, or report the claimed HuB and HuC deletion-mutant splicing result. No page number was available for the passage. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

HuR mRNA has three polyadenylation variants (1.5, 2.4, and 6.0 kb) that differ in 3′ UTR length.

“Mansfield and Keene showed that there are three different HuR mRNA polyadenylation variants (1.5, 2.4, and 6.0 kb), which differ in 3′ UTR length.”

• cites Mansfield and Keene 2011 sourceSupported

All four Hu members bind and block U-rich sequences near the 2.4-kb polyadenylation site and thereby promote expression of the 6.0-kb HuR transcript.

“All four Hu members were found to bind and block U-rich sequences near the 2.4-kb polyadenylation site and thereby promote expression of the 6.0-kb transcript.”

• cites Mansfield and Keene 2011 sourcePartly supported

  The Results report that all four Hu proteins bind near the 2.4-kb polyadenylation site and that Hu-protein overexpression increases the 6.0-kb HuR transcript. But the Results describe interference with polyadenylation as potential and say they could not definitively prove a direct effect. The claim overstates the evidence by saying all four were found to block the site and thereby promote the longer transcript. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Repression of Ins2 translation by HuD is likely required to maintain insulin homeostasis.

“On the other hand, the study by Lee et al. showed that the repression of Ins2 translation by HuD is likely required to maintain insulin homeostasis (Lee et al. 2012).”

• cites Lee et al. 2012 sourceSupported

HuD is capable of repressing protein synthesis, as shown for p27 and preproinsulin (Ins2) mRNAs.

“In addition to enhancing translation, HuD is capable of repressing protein synthesis, as shown for p27 and preproinsulin (Ins2) mRNAs (Kullmann et al. 2002; Lee et al. 2012).”

• cites Kullmann et al. 2002 sourceSupported
• cites Lee et al. 2012 sourceSupported

HuR interacts with AUF1, KSRP, and TIA-1 in the nucleus and cytoplasmic stress granules.

“Fluorescence resonance energy transfer (FRET) and biochemical techniques revealed that HuR interacts with AUF1, KSRP, and TIA-1 in the nucleus and cytoplasmic stress granules (David et al. 2007; David Gerecht et al. 2010).”

• cites David et al. 2007 sourcePartly supported

  The section on FRET-detected complexes reports a HuR–p37AUF1 interaction in the nucleus. But the stress-granule section says HuR colocalizes with TIA-1 while AUF1 does not enter the granules; colocalization does not establish an interaction with TIA-1. The paper mentions KSRP but does not report a HuR–KSRP interaction. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites David Gerecht et al. 2010 sourceSupported

Currently, there are only three known pathways that regulate the abundance or function of HuD: protein kinase C (PKC), coactivator-associated arginine methyltransferase 1 (CARM1), and protein kinase B (PKB/AKT).

“Currently, there are only three known pathways that regulate the abundance or function of HuD: protein kinase C (PKC) (Mobarak et al. 2000; Pascale et al. 2005; Lim and Alkon 2012); coactivator-associated arginine methyltransferase 1 (CARM1) (Fujiwara et al. 2006; Hubers et al. 2010); and protein kinase B (PKB/AKT) (Fujiwara et al. 2011a).”

• cites Mobarak et al. 2000 sourcePartly supported

  The Mobarak et al. citation is attached to the PKC pathway, not to CARM1 or PKB/AKT. The Discussion says PKC likely controls HuD function, but presents this as an inference rather than an established regulatory pathway; its experiments establish HuD’s role in PKC-dependent neurite outgrowth in PC12 cells. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites Fujiwara et al. 2006 sourceSupported
• cites Fujiwara et al. 2011aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The ability of HuD to control early differentiation processes requires post-transcriptional regulation of specific target transcripts such as mRNAs encoding cyclin-dependent kinase p21cip1/waf1.

“The ability of HuD to control these early differentiation processes requires post-transcriptional regulation of specific target transcripts such as mRNAs encoding cyclin-dependent kinase p21cip1/waf1 (Fujiwara et al. 2006).”

• cites Fujiwara et al. 2006 sourcePartly supported

  The Results show that HuD protects p21cip1/waf1 mRNA from decay, and the paper links reduced HuD methylation with slower growth and neurite outgrowth in PC12 cells. But the Discussion describes HuD’s protective effect on differentiation-related transcripts as presumed; it does not establish that regulation of p21cip1/waf1 is required for HuD to control early differentiation. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

HuD is important for inhibition of neuronal stem/progenitor cell self-renewal in vivo.

“illustrating in vivo the importance of HuD for inhibition of neuronal stem/progenitor cell self-renewal (Akamatsu et al. 2005).”

• cites Akamatsu et al. 2005 sourceSupported

HuD has an essential role in terminal differentiation, namely dendritic and axonal outgrowth.

“Studies in which HuD levels were down-regulated or over-expressed in cultured cells have revealed an essential role for HuD in terminal differentiation, namely dendritic and axonal outgrowth (Wakamatsu and Weston 1997; Aranda-Abreu et al. 1999; Mobarak et al. 2000; Anderson et al. 2001; Hubers et al. 2010).”

• cites Wakamatsu and Weston 1997 sourceNot checked — no full text of the source
• cites Aranda-Abreu et al. 1999 sourcePartly supported

  The section on r-HuD antisense treatment reports that reducing HuD caused neurite retraction in NGF-treated PC12 cells, supporting a role in neurite outgrowth. The Discussion explicitly says this model produces neurite extension, not defined dendrites and axons, so this paper does not establish the claim's more specific dendritic and axonal outgrowth. Page numbers were not provided for these passages. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Mobarak et al. 2000 sourcePartly supported

  The Results and Discussion show that reducing HuD impairs NGF- and PKC-dependent neurite outgrowth in PC12 cells, while overexpressing HuD promotes process outgrowth. But the study examines early, immature neurites rather than establishing an essential role in terminal differentiation or specifically in both dendritic and axonal outgrowth; cAMP-dependent outgrowth remains intact. Page numbers are not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Adult HuD−/− mice contain an increased number of self-renewing cells in the subventricular zone (SVZ).

“Adult HuD−/− mice were also found to contain an increased number of self-renewing cells in the subventricular zone (SVZ), illustrating in vivo the importance of HuD for inhibition of neuronal stem/progenitor cell self-renewal (Akamatsu et al. 2005).”

• cites Akamatsu et al. 2005 sourceSupported

FoxO1 negatively regulates transcription of HuD under low glucose conditions in pancreatic β cells.

“whereas FoxO1 was recently found to negatively regulate transcription of HuD under low glucose conditions in pancreatic β cells (Lee et al. 2012).”

• cites Lee et al. 2012 sourceSupported

These variants encode transcripts exhibiting unique temporal expression during Xenopus nervous system development.

“These variants encode transcripts exhibiting unique temporal expression during Xenopus nervous system development (Nassar 2011).”

• cites Nassar 2011 sourceSupported

HuD has a possible role in spinal muscular atrophy (SMA).

“Also of particular relevance is the possible role of HuD in spinal muscular atrophy (SMA), a disease that results in degeneration of spinal cord motor neurons due to deletion or loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene, resulting in inadequate expression of functional SMN protein (Burghes and Beattie 2009).”

• cites Burghes and Beattie 2009 sourcePartly supported

  The Introduction and Abstract support the sentence’s description of SMA as a motor-neuron disorder caused by loss or mutation of SMN1 and reduced SMN protein. Our copy does not mention HuD or propose a role for it in SMA (searched: HuD, ELAVL4), so it does not support that part of the claim. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Expression of nELAV proteins and GAP-43 mRNA increased in the cytoskeletal and membrane fractions of murine hippocampal neurons following spatial discrimination tasks.

“The first studies to link HuD to learning and memory demonstrated that expression of nELAV proteins and GAP-43 mRNA increased in the cytoskeletal and membrane fractions of murine hippocampal neurons following spatial discrimination tasks (Quattrone et al. 2001; Pascale et al. 2004).”

• cites Quattrone et al. 2001 sourcePartly supported

  The Results and Discussion report increased neuronal ELAV-like protein in the membrane and especially cytoskeletal fractions of hippocampi from radial-maze-trained mice. They also report learning-associated up-regulation of GAP-43 mRNA, but do not show that its increase occurred in those fractions; the fraction-specific finding concerns the proteins. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Pascale et al. 2004 sourcePartly supported

  The Discussion reports earlier up-regulation of neuronal ELAV proteins after a mouse spatial task, while this paper's Results examine rats trained in the Morris water maze. The Results show increased ELAV-like proteins chiefly in the cytoskeletal fraction and increased GAP-43 mRNA in the hippocampus. The membrane and cytoskeletal fraction increases reported for GAP-43 concern its protein, not its mRNA; the ELAV-like protein increase had no membrane contribution. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

nELAVs have recently been linked to Alzheimer's disease.

“In accordance with its direct or indirect function in learning and memory, nELAVs have recently been linked to Alzheimer’s disease (AD), a condition characterized by neuronal death, memory loss and eventual dementia.”

• cites Amadio et al. 2009 sourceSupported

HuD protein levels, as well as a cohort of its target mRNAs such as GAP-43, CAMKIIα and Homer, increase in several brain regions including the dentate gyrus (DG) following neurotoxin-induced seizure.

“In parallel with this potential role, studies have demonstrated that HuD protein levels, as well as a cohort of its target mRNAs such as GAP-43, CAMKIIα and Homer, increase in several brain regions including the dentate gyrus (DG) following neurotoxin-induced seizure (Bolognani et al. 2007a; Tiruchinapalli et al. 2008a; Winden et al. 2011).”

• cites Bolognani et al. 2007aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Tiruchinapalli et al. 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Winden et al. 2011 sourcePartly supported

  The Results (‘Mechanisms of neuronal response to seizures’; page not available) report increased HuD expression by qRT-PCR in both hemispheres of animals with chronic seizures and an association between HuD target genes and seizures. The paper uses a kainic-acid seizure model focused on the hippocampus and dentate gyrus, but these passages do not establish increased HuD protein levels, increases in the named target mRNAs, or increases across several brain regions. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Overexpression of HuD or of one of its target mRNAs (cpg-15) partially rescues SMA-like defects related to cell morphology and recruitment of specific mRNAs into RNA granules.

“Importantly, overexpression of HuD or of one of its target mRNAs (cpg-15) was found to partially rescue SMA-like defects related to cell morphology and recruitment of specific mRNAs into RNA granules (Hubers et al. 2010; Akten et al. 2011).”

• cites Hubers et al. 2010 sourceNot checked — no full text of the source
• cites Akten et al. 2011 sourcePartly supported

  The Results (page not specified) report that cpg15 mRNA overexpression partially rescued motor-axon defects in SMN-deficient zebrafish, supporting the morphology portion of the claim. The paper identifies HuD as an SMN-interacting protein but does not report rescue by HuD overexpression or rescue of mRNA recruitment into RNA granules. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

HuD−/− mice have a transient impairment in neurite extension of several cranial nerves around day 10.5 of embryonic development.

“Conversely, detailed analysis of HuD−/− mice revealed a transient impairment in neurite extension of several cranial nerves around day 10.5 of embryonic development (Akamatsu et al. 2005).”

• cites Akamatsu et al. 2005 sourceSupported

HuD interacts with SMN protein in axonal compartments of neurons.

“A series of cell imaging and biochemical experiments in three independent studies demonstrated that HuD interacts with SMN protein in axonal compartments of neurons (Hubers et al. 2010; Akten et al. 2011; Fallini et al. 2011).”

• cites Hubers et al. 2010 sourceNot checked — no full text of the source
• cites Akten et al. 2011 sourceSupported
• cites Fallini et al. 2011 sourceSupported

The interaction between nELAV proteins and ADAM10 mRNA is disrupted following exposure to Aβ1-42 leading to reduced ADAM10 protein levels.

“The authors also determined that the interaction between nELAV proteins and ADAM10 mRNA was disrupted following exposure to Aβ1–42 leading to reduced ADAM10 protein levels (Amadio et al. 2009).”

• cites Amadio et al. 2009 sourcePartly supported

  The Results report that Aβ1–42 exposure disrupted detectable nELAV–ADAM10 mRNA binding and reduced ADAM10 protein levels. The Discussion says the reduced protein expression may result from disrupted binding, but notes that post-translational effects cannot be excluded. Thus, the causal link implied by “leading to” is stronger than the paper establishes (page numbers not supplied). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Kainic acid-induced seizures in rats increase HuD and several of its target mRNAs.

“A third study assessed gene expression using microarray platforms to show that HuD and several of its target mRNAs increased following kainic acid-induced seizures in rats (Winden et al. 2011).”

• cites Winden et al. 2011 sourceSupported

Ngn2 binds the two E-boxes in the conserved upstream region to promote expression of HuD only in cells differentiating into neurons.

“Importantly, using a combination of promoter-reporter assays, chromatin IPs, and electrophoretic mobility shift assays, we showed that Ngn2 binds these two E-boxes to promote expression of HuD only in cells differentiating into neurons.”

E1c is the predominantly expressed E1 variant.

“Moreover, our data suggest that E1c is the predominantly expressed E1 variant (Bronicki et al. 2012).”

• cites Bronicki et al. 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The mammalian HuD gene contains eight E1 variants that are well conserved among higher vertebrates.

“Work in our laboratory has shown that the mammalian HuD gene actually contains eight E1 variants that are well conserved among higher vertebrates, adding to the speculation that multiple promoters control HuD expression (Bronicki et al. 2012).”

• cites Bronicki et al. 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD E1 variants may encode alternate HuD N termini.

“We also found that most E1 variants house an in-frame methionine codon (with the exception of E1a4, since it harbors two stop codons downstream from the AUG), suggesting that they may encode alternate HuD N termini.”

The combinatorial complexity of HuD alternative 5′ and 3′ exons may produce up to 24 different mRNA variants.

“The combinatorial complexity of HuD alternative 5′ and 3′ exons may produce up to 24 different mRNA variants.”

Three novel consensus motifs are present in approximately 80% of HuD-targeted mRNAs expressed in the mouse forebrain.

“Instead, the investigators identified three novel consensus motifs that are present in ∼80% of HuD-targeted mRNAs expressed in the mouse forebrain.”

• cites Bolognani et al. 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The third RRM of HuD interacts with other proteins, including homo- and hetero-multimerizing with Hu members.

“Another function of the third RRM of HuD involves interacting with other proteins, including homo- and hetero-multimerizing with Hu members (Kasashima et al. 2002).”

• cites Kasashima et al. 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

At the subcellular level, HuD is predominantly expressed in the cytoplasm, with minor levels detected in the nucleus.

“At the subcellular level, HuD is predominantly expressed in the cytoplasm, with minor levels detected in the nucleus (Kasashima et al. 1999).”

• cites Kasashima et al. 1999 sourceNot checked — no full text of the source

HuD is localized to granules, along with other proteins such as KIF3A and SMN, within the cytoplasm and neurites.

“Closer inspection of intraneuronal compartments revealed that HuD is localized to granules, along with other proteins, such as kinesin-like protein (KIF3A) and survival of motoneuron (SMN), within the cytoplasm and neurites (Aronov et al. 2002; Smith et al. 2004; Tiruchinapalli et al. 2008a,b; Hubers et al. 2010; Akten et al. 2011; Fallini et al. 2012b).”

• cites Aronov et al. 2002 sourceNot checked — no full text of the source
• cites Smith et al. 2004 sourceNot checked — no full text of the source
• cites Tiruchinapalli et al. 2008a,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A microarray screen of HuD-bound mRNAs found that less than half of its targets contain an ARE.

“Interestingly, a microarray screen of HuD-bound mRNAs found that less than half of its targets contain an ARE (Bolognani et al. 2010).”

• cites Bolognani et al. 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The amino acid residues interacting with RNA nucleotides are well conserved among all Hu proteins and the Drosophila ELAV protein.

“This report also showed that the amino acid residues interacting with RNA nucleotides are well conserved among all Hu proteins and the Drosophila ELAV protein.”

• cites Wang and Tanaka Hall 2001 sourceNot checked — no full text of the source

The crystal structure of HuD bound to c-fos or TNFα mRNAs illustrates that specific residues within its first two RRMs preferentially bind the pyrimidine-rich X-U/C-U-X-X-U/C?-U-U/C consensus sequence.

“The crystal structure of HuD bound to c-fos or tumor necrosis factor α (TNFα) mRNAs illustrates that specific residues within its first two RRMs preferentially bind the pyrimidine-rich X-U/C-U-X-X-U/C?-U-U/C consensus sequence where the “?” denotes ambiguity whether a cytosine in this position is tolerated (Wang and Tanaka Hall 2001).”

• cites Wang and Tanaka Hall 2001 sourceNot checked — no full text of the source

HuD, along with the other nELAV proteins, can promote or suppress exon inclusion by interacting with or antagonizing splicing, transcription, and chromatin components.

“Altogether, these studies clearly demonstrate that HuD, along with the other nELAV proteins, can promote or suppress exon inclusion by interacting with (or antagonizing) splicing, transcription, and chromatin components (Fig. 2A).”

HuD increases the half-lives of various neuronal transcripts.

“Since these initial findings, HuD has emerged as the best-described stabilizing RBP in neurons, as evidenced by the numerous studies outlining its role in increasing the half-lives of various neuronal transcripts (Fig. 2C).”

HuD binds specifically to an ARE sequence in the c-fos 3′ UTR.

“Using REMSAs, the authors showed that HuD binds specifically to an ARE sequence in the c-fos 3′ UTR.”

• cites Liu et al. 1995 sourceNot checked — no full text of the source

One likely mechanism through which HuD and other Hu members stabilize mRNAs involves antagonizing destabilizing RBPs such as AUF1 from binding to cis-acting elements.

“One likely mechanism through which HuD and other Hu members stabilize mRNAs involves antagonizing destabilizing RBPs such as AUF1 from binding to cis-acting elements (Barreau et al. 2006).”

• cites Barreau et al. 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Cytoplasmic shuttling of HuD requires the NES region.

“Overexpression of wild-type and deletion mutant HuD proteins revealed that cytoplasmic shuttling of HuD requires the NES region (Kasashima et al. 1999).”

• cites Kasashima et al. 1999 sourceNot checked — no full text of the source

HuD contains a NES and putative NLS located in the variable linker domain between the second and third RRM, which permit nucleocytoplasmic shuttling of HuD.

“As previously mentioned, HuD contains a NES and putative NLS located in the variable linker domain, between the second and third RRM, which permit nucleocytoplasmic shuttling of HuD (Fig. 2B; Kasashima et al. 1999).”

• cites Kasashima et al. 1999 sourceNot checked — no full text of the source

HuD binds short-lived mRNAs whose protein product functions in cell proliferation, such as N-myc and c-myc.

“Numerous other ARE-harboring transcripts, such as N-myc and c-myc, were later identified as targets of HuD using similar in vitro approaches, indicating that HuD binds short-lived mRNAs whose protein product functions in cell proliferation (Liu et al. 1995; Ross et al. 1997).”

• cites Liu et al. 1995 sourceNot checked — no full text of the source
• cites Ross et al. 1997 sourceNot checked — no full text of the source

HuD binds to eIF4A and the poly(A) tail of transcripts, via its linker region and third RRM, to enhance cap-dependent protein synthesis.

“Complementary to its role in mRNA localization, evidence for the direct involvement of HuD in regulating translation was unveiled when Fukao and colleagues showed that HuD binds to eIF4A and the poly(A) tail of transcripts, via its linker region and third RRM, to enhance cap-dependent protein synthesis (Fukao et al. 2009).”

• cites Fukao et al. 2009 sourceNot checked — no full text of the source

PKC activation negatively controls CARM1-mediated methylation of HuD to promote neuronal differentiation.

“This study clearly illustrates that PKC activation negatively controls CARM1-mediated methylation of HuD to promote neuronal differentiation.”

The PI3K/AKT1 pathway regulates HuD function at the translational level.

“The phosphatidylinositol 3-kinase (PI3K)/AKT1 pathway was also found to regulate HuD function, specifically at the translational level (Fujiwara et al. 2011a).”

• cites Fujiwara et al. 2011aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Activating classical PKC isoforms and simultaneously blocking CARM1 activity potentiates HuD binding to target mRNAs and hippocampal neurite extension.

“Furthermore, activating the classical PKC isoforms and simultaneously blocking CARM1 activity potentiates HuD binding to target mRNAs and hippocampal neurite extension.”

• cites Lim and Alkon 2012 sourceNot checked — no full text of the source

AKT1 positively controls HuD expression.

“suggesting that AKT1 also positively controls HuD expression”

In hippocampal neurons, activated PKC isoforms interact and phosphorylate CARM1, leading to decreased CARM1 methyltransferase activity.

“In hippocampal neurons, the study demonstrated using pathway-specific inhibitors that activated PKC isoforms interact and phosphorylate CARM1, which leads to decreased CARM1 methyltransferase activity.”

• cites Lim and Alkon 2012 sourceNot checked — no full text of the source

Chronic (7-day) activation of AKT1 enhances HuD protein levels.

“In addition to binding HuD, chronic (7-day) activation of AKT1 enhances HuD protein levels, suggesting that AKT1 also positively controls HuD expression (Tiruchinapalli et al. 2008a).”

• cites Tiruchinapalli et al. 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Stabilization of Tau and p27 mRNAs requires additional post-translational modifications of HuD and/or other trans-acting factors.

“suggesting that stabilization of these other target mRNAs requires additional post-translational modifications of HuD and/or other trans-acting factors”

GAP-43 and Tau colocalize with HuD protein and polysomes in growth cones during neuronal differentiation.

“For example, two target mRNAs of HuD involved in axonal outgrowth, namely GAP-43 and Tau, were found to colocalize with HuD protein and polysomes in growth cones during neuronal differentiation (Smith et al. 2004; Atlas et al. 2007).”

• cites Smith et al. 2004 sourceNot checked — no full text of the source
• cites Atlas et al. 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Both stabilizing and destabilizing RBPs can bind the same transcript simultaneously.

“However, there is evidence indicating that this mechanism is more complex since both stabilizing and destabilizing RBPs can bind the same transcript simultaneously.”

This mechanism is important for HuD-dependent neurite extension in PC12 cells.

“Moreover, this mechanism was determined to be important for HuD- dependent neurite extension in PC12 cells.”

• cites Fukao et al. 2009 sourceNot checked — no full text of the source

HuD interacts with a host of mRNP components involved in transport and translation in the cytoplasm and neurites, such as KIF3A, IMP-1, SMN, PABP, eEF4E, and MAP1B.

“Co-IP and immunocytochemistry experiments revealed that HuD interacts with a host of mRNP components involved in transport and translation in the cytoplasm and neurites such as the motor protein KIF3A (Aronov et al. 2002), IGF-II mRNA binding protein 1 (IMP-1) (Atlas et al. 2004, 2007), survival of motor neuron (SMN) (Hubers et al. 2010; Akten et al. 2011; Fallini et al. 2011), poly(A) binding”

• cites Aronov et al. 2002 sourceNot checked — no full text of the source
• cites Atlas et al. 2004, 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Hubers et al. 2010 sourceNot checked — no full text of the source

The 3′ UTR of Xenopus HuD homolog elrD contains an ∼100-nt stretch with 90% identity to the human HuD 3′ UTR.

“Analysis of the Xenopus HuD homolog elrD sequence illustrated that the 3′ UTR contains an ∼100-nt stretch of nucleotides with 90% identity to the human HuD 3′ UTR, implying that this fragment encompasses an important evolutionarily conserved regulatory structure and/or cis-element(s) (Good 1995).”

• cites Good 1995 sourceNot checked — no full text of the source

The Drosophila ELAV auto-regulatory mechanism occurs when ELAV levels pass a certain threshold, resulting in increased ELAV binding to an AU-rich site in a noncoding 3′-terminal exon and production of a noncoding transcript.

“This auto-regulatory mechanism is thought to occur when ELAV levels pass a certain threshold, resulting in increased ELAV binding to an AU-rich site in a noncoding 3′-terminal exon and production of a noncoding transcript (Borgeson and Samson 2005).”

• cites Borgeson and Samson 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Ngn2-dependent control of HuD transcription is central to neuronal development, function, and dysfunction.

“Given the established function of Ngn2 in neurogenesis (Guillemot 2007) and its emerging roles in learning and memory (Galichet et al. 2008) and neuronal diseases (Rostomily et al. 1997; Andersson et al. 2006; Kele et al. 2006; Uhrig et al. 2009), our findings suggest that Ngn2-dependent control of HuD transcription is central to neuronal development, function, and dysfunction (Fig. 4D).”

• cites Guillemot 2007 sourceNot checked — no full text of the source
• cites Galichet et al. 2008 sourceNot checked — no full text of the source
• cites Rostomily et al. 1997Not checked — no full text of the source

The developmental regulation and function of mouse E1b and E1c is evolutionarily conserved.

“implying that the developmental regulation and function of these two mammalian exons is evolutionarily conserved”

HuD transcripts are likely subjected to intricate post-transcriptional control involving RBPs and miRs.

“Altogether, these studies stress that HuD transcripts are likely subjected to intricate post-transcriptional control involving RBPs and miRs.”

The 5′ genomic region of elrD contains two distinct promoters that drive neuron-specific expression of two E1 variants, E1 and E′1.

“In line with this possibility, the 5′ genomic region of elrD was demonstrated to contain two distinct promoters that drive neuron-specific expression of two E1 variants, E1 and E′1 (Nassar and Wegnez 2001).”

• cites Nassar and Wegnez 2001 sourceNot checked — no full text of the source

The stability and translation of mature HuD mRNA is negatively controlled by miR-375 and potentially other trans-acting factors.

“The stability and translation of mature HuD mRNA is negatively controlled by miR-375 and potentially other trans-acting factors.”

HuD binds to its own transcript in the mouse forebrain.

“Indeed, analysis of HuD-targeted mRNAs in the mouse forebrain showed that HuD binds to its own transcript, although the role of this interaction remains unknown (Bolognani et al. 2010).”

• cites Bolognani et al. 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD acts as a master regulator of various neuronal processes.

“The multiple post-transcriptional effects exerted by HuD on mRNAs whose proteins have key roles in neurons (Table 2) and its expansive spatiotemporal expression within the nervous system strongly suggest that HuD acts as a “master regulator” of various neuronal processes (Deschenes-Furry et al. 2006; Perrone-Bizzozero and Bird 2013).”

• cites Deschenes-Furry et al. 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Perrone-Bizzozero and Bird 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Transgenic mice ectopically expressing HuD in forebrain neurons under the control of the CAMKIIα promoter contain increased mossy fiber length.

“In support of these findings, transgenic mice ectopically expressing HuD (HuD-Tg) in forebrain neurons under the control of the CAMKIIα promoter (Bolognani et al. 2007b) were shown to contain increased mossy fiber length (Perrone-Bizzozero et al. 2011).”

• cites Bolognani et al. 2007bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Perrone-Bizzozero et al. 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

During neuronal development, transcription of the HuD gene is positively regulated by the Ngn2-E47 heterodimer binding to E-boxes upstream of E1c.

“During neuronal development transcription of the HuD gene is positively regulated by the Ngn2-E47 heterodimer binding to E-boxes upstream of E1c.”

Induction of HuD during early neuronal differentiation of P19 cells is under neuron-specific transcriptional control.

“Research in our laboratory has revealed that the induction of HuD during early neuronal differentiation of P19 cells, a multipotent embryonal carcinoma cell line, is under neuron-specific transcriptional control (Bronicki et al. 2012).”

• cites Bronicki et al. 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Knockdown of miR-375 in cultured cells and mouse brain prevents neurite outgrowth through negative control of HuD expression.

“Knockdown of miR-375 in cultured cells and mouse brain revealed that this microRNA prevents neurite outgrowth through negative control of HuD expression.”

• cites Abdelmohsen et al. 2010 sourceNot checked — no full text of the source

HuD controls almost all stages of a neuron's existence, including neuronal commitment, differentiation, and activity.

“Multiple studies on primary and cultured neuronal cells have demonstrated that HuD controls almost all stages of a neuron’s existence, including neuronal commitment, differentiation, and activity (Deschenes-Furry et al. 2006; Pascale and Govoni 2012).”

• cites Deschenes-Furry et al. 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Pascale and Govoni 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD-dependent neurogenesis requires commitment of cells to the neuronal lineage.

“Moreover, HuD-dependent neurogenesis requires commitment of cells to the neuronal lineage since ectopic expression of HuD in nonneuronal cells does not result in neuronal differentiation (Wakamatsu and Weston 1997).”

• cites Wakamatsu and Weston 1997 sourceNot checked — no full text of the source

HuD-Tg mice express HuD throughout the forebrain, including the hippocampus and cerebral cortex.

“To further study the role of HuD in learning and memory, HuD-Tg mice were employed since these mice express HuD throughout the forebrain, including the hippocampus and cerebral cortex (Bolognani et al. 2006).”

• cites Bolognani et al. 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The eventual up-regulation of endogenous HuD levels post-nerve injury may be involved in axonal recovery following nerve damage.

“These two studies provide a strong indication that the eventual up-regulation of endogenous HuD levels post-nerve injury may be involved in axonal recovery following nerve damage.”

Several HuD-targeted mRNAs encode synaptic proteins.

“Along with the finding that several HuD-targeted mRNAs encode synaptic proteins (Bolognani et al. 2010), these studies indicate that HuD is important for various types of neuronal plasticity, potentially by directly acting at the synapse.”

• cites Bolognani et al. 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Three separate cohort genetic studies have linked single nucleotide polymorphisms (SNPs) within the HuD locus to the development of Parkinson's disease.

“In addition to its potential role in AD, three separate cohort genetic studies have linked single nucleotide polymorphisms (SNPs) within the HuD locus to the development of Parkinson’s disease (PD), a degenerative disorder of the CNS.”

• cites Noureddine et al. 2005 sourceNot checked — no full text of the source
• cites Haugarvoll et al. 2007 sourceNot checked — no full text of the source
• cites DeStefano et al. 2008 sourceNot checked — no full text of the source

Precise spatiotemporal control of HuD levels is necessary for proper learning and memory.

“Based on these findings, it was concluded that the precise spatiotemporal control of HuD levels is necessary for proper learning and memory.”

The rs967582 SNP is associated with increased risk of PD in a Caucasian population.

“Last, a subsequent study employed samples from a Caucasian population to confirm that the rs967582 SNP is associated with increased risk of PD (DeStefano et al. 2008).”

• cites DeStefano et al. 2008 sourceNot checked — no full text of the source

Microarray analysis of HuD-targeted mRNAs in DGCs demonstrated that HuD-Tg mice contained increased expression of transcripts whose products regulate neuronal development and axogenesis.

“Furthermore, as mentioned above, microarray analysis of HuD-targeted mRNAs in DGCs demonstrated that HuD-Tg mice contained increased expression of transcripts whose products regulate neuronal development and axogenesis (Perrone-Bizzozero et al. 2011).”

• cites Perrone-Bizzozero et al. 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD has been implicated in axonal regeneration in two models of nerve injury.

“Additionally, HuD has been implicated in axonal regeneration in two models of nerve injury.”

• cites Deschenes-Furry et al. 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Anderson et al. 2003 sourceNot checked — no full text of the source

The reduction in AChE mRNA abundance following axotomy could be rescued by localized overexpression of HuD delivered via a viral vector.

“Importantly, the reduction in AChE mRNA abundance could be rescued by localized overexpression of HuD delivered via a viral vector.”

• cites Deschenes-Furry et al. 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD plays a role in different types of neuronal plasticity.

“Increasing evidence suggests that HuD also plays a role in different types of neuronal plasticity.”

Nerve crush of dorsal root ganglion (DRG) neurons resulted in an increase of HuD protein and GAP-43 mRNA expression within 7 d, lasting up to 21 d post-injury.

“Although HuD expression was shown to decrease immediately following nerve injury, another study performed nerve crush of dorsal root ganglion (DRG) neurons which resulted in an increase of HuD protein and GAP-43 mRNA expression within 7 d, lasting up to 21 d post-injury (Anderson et al. 2003).”

• cites Anderson et al. 2003 sourceNot checked — no full text of the source

Misregulation or misexpression of HuD is implicated in several neural pathologies and tumors.

“Given its multiple important roles in neurons, it is not surprising that misregulation or misexpression of HuD is implicated in several neural pathologies and tumors (Pascale and Govoni 2012; Perrone-Bizzozero and Bird 2013).”

• cites Pascale and Govoni 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Perrone-Bizzozero and Bird 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD positively regulates neurite outgrowth.

“These studies provide a clear demonstration that HuD positively regulates neurite outgrowth.”

HuD protein levels increased in somatic and dendritic compartments of hilar and CA3 hippocampal neurons following contextual fear conditioning.

“Closer inspection of HuD expression revealed increased HuD protein levels in somatic and dendritic compartments of hilar and CA3 hippocampal neurons following a different learning paradigm, contextual fear conditioning (Bolognani et al. 2004).”

• cites Bolognani et al. 2004 sourceNot checked — no full text of the source

Increases in HuD levels after nerve injury may facilitate regeneration.

“Thus increases in HuD levels after nerve injury may facilitate regeneration.”

Two SNPs (rs967582 and rs2494876) were associated with age at onset of PD in a Caucasian population.

“The first of these studies genotyped nine SNPs in the HuD gene locus from a Caucasian population and found that two of them, one in the first intron (rs967582) and one in the coding region (rs2494876), were associated with age at onset (AAO) of PD (Noureddine et al. 2005).”

• cites Noureddine et al. 2005 sourceNot checked — no full text of the source

In the same chronic schizophrenia samples, the abundance of several mRNAs, including those encoding proteins involved in neuronal development, synaptic plasticity, and neurotransmission, is increased.

“The authors also found that there was augmented abundance of several mRNAs including those encoding proteins involved in neuronal development, synaptic plasticity, and neurotransmission.”

• cites Hakak et al. 2001 sourceNot checked — no full text of the source

TDP-43-containing cytoplasmic aggregates sequester HuD.

“Biochemical and cell imaging techniques were used to demonstrate that TDP-43 associates with HuD and that TDP-43-containing cytoplasmic aggregates sequester HuD, suggesting that misregulation of mRNA metabolism in the cytoplasm of motor neurons could be involved in the development of ALS (Fallini et al. 2012a).”

• cites Fallini et al. 2012aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Deletions or mutations of the HuD gene are associated with the etiology or progression of certain neuroendocrine cancers.

“Together, these findings imply that deletions or mutations of the HuD gene are associated with the etiology or progression of certain neuroendocrine cancers.”

After seizures, several HuD-targeted mRNAs such as GAP-43 and Neuritin increase.

“Furthermore, this study illustrated via RNA IP and quantitative RT-PCR that several HuD-targeted mRNAs such as GAP-43 and Neuritin also increased after seizures.”

• cites Tiruchinapalli et al. 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Aberrant expression or function of HuD has been detected in several cancers of the central and peripheral nervous system, most prominently neuroblastomas and small cell lung cancers.

“Aberrant expression or function of HuD has been detected in several cancers of the central and peripheral nervous system, most prominently NBs and SCLCs (Szabo et al. 1991; Dalmau et al. 1992; Chagnovich and Cohn 1996; Ball and King 1997; Schramm et al. 1999; Stawski et al. 2012).”

• cites Szabo et al. 1991 sourceNot checked — no full text of the source
• cites Dalmau et al. 1992 sourceNot checked — no full text of the source
• cites Chagnovich and Cohn 1996 sourceNot checked — no full text of the source

In patients with chronic schizophrenia, HuD transcript levels are increased in the dorsolateral prefrontal cortex.

“One study employed a DNA microarray on samples from patients with chronic schizophrenia and determined that HuD transcript levels were increased in the dorsolateral prefrontal cortex (Hakak et al. 2001).”

• cites Hakak et al. 2001 sourceNot checked — no full text of the source

HuD expression is elaborately regulated at the transcriptional and post-transcriptional levels.

“An emerging picture reveals elaborate regulation of HuD expression, notably at the transcriptional and post-transcriptional levels”

Kainic acid-induced seizures in adult male rats produce increased HuD and GAP-43 mRNA levels in the dentate gyrus.

“Using kainic acid to induce seizures in adult male rats, one study found that this treatment produced increased HuD and GAP-43 mRNA levels in the DG (Bolognani et al. 2007a).”

• cites Bolognani et al. 2007aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

High levels of HuD and other nELAVs in neuroblastomas are associated with a clinically favorable prognosis.

“Conversely, high levels of HuD and other nELAVs in NBs have been associated with a clinically favorable prognosis (Ball and King 1997).”

• cites Ball and King 1997Not checked — no full text of the source

TDP-43 associates with HuD.

“Biochemical and cell imaging techniques were used to demonstrate that TDP-43 associates with HuD and that TDP-43-containing cytoplasmic aggregates sequester HuD, suggesting that misregulation of mRNA metabolism in the cytoplasm of motor neurons could be involved in the development of ALS (Fallini et al. 2012a).”

• cites Fallini et al. 2012aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD targets specific mRNAs to regulate multiple levels of their metabolism, including nuclear processing, mRNA stability, and translation.

“HuD targets specific mRNAs to regulate multiple levels of their metabolism, including nuclear processing, mRNA stability, and translation.”

Degenerating motor neurons in ALS patients commonly display cytoplasmic aggregates containing the DNA/RNA-binding protein TDP-43.

“Degenerating motor neurons in ALS patients commonly display cytoplasmic aggregates containing the DNA/RNA-binding protein TDP-43 (Neumann et al. 2006).”

• cites Neumann et al. 2006 sourceNot checked — no full text of the source

Some mRNAs whose abundance is increased in chronic schizophrenia, such as GAP-43, are targets of HuD.

“Interestingly, some of these mRNAs, such as GAP-43, are targets of HuD”

• cites Perrone-Bizzozero and Bird 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Pilocarpine-induced seizure increases dendritic localization of HuD in hippocampal neurons.

“Another report used immunocytochemistry and Western blot techniques to demonstrate increased dendritic localization of HuD in hippocampal neurons following pilocarpine-induced seizure (Tiruchinapalli et al. 2008a).”

• cites Tiruchinapalli et al. 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Misregulation of mRNA metabolism in the cytoplasm of motor neurons could be involved in the development of ALS.

“suggesting that misregulation of mRNA metabolism in the cytoplasm of motor neurons could be involved in the development of ALS (Fallini et al. 2012a).”

• cites Fallini et al. 2012aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In approximately 40% of neuroblastoma tumors, there is a partial or complete deletion of the short arm (p) in one chromosome 1 homolog, which encompasses the HuD gene locus.

“For instance, in ∼40% of NB tumors, there is a partial or complete deletion of the short arm (p) in one chromosome 1 homolog, which encompasses the HuD gene locus (Muresu et al. 1994; Maris et al. 1995).”

• cites Muresu et al. 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Maris et al. 1995Not checked — no full text of the source

HuD has recently been associated with amyotropic lateral sclerosis (ALS).

“In line with its potential role in SMA, HuD has recently been associated with amyotropic lateral sclerosis (ALS), a neurodegenerative disorder resulting in progressive and fatal deterioration of upper and lower motor neurons (Pratt et al. 2012).”

• cites Pratt et al. 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

HuD has key roles in neurons, among which neuronal differentiation is the best described.

“Through post-transcriptional regulation of various neuronal mRNAs, HuD has key roles in neurons, among which neuronal differentiation is the best described.”