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

In the paper

“Surprisingly, although reduced CARM1 levels also increased GAP-43 mRNA expression, they had no effect on other known HuD-targeted mRNAs, including Tau and p27, suggesting that stabilization of these other target mRNAs requires additional post-translational modifications of HuD and/or other trans-acting factors (Fujiwara et al. 2006; Hubers et al. 2010).”

What the sources say

• Disputed

  The Discussion says CARM1 knockdown had no effect on GAP43, tau, or p27 transcript levels; only p21cip1/waf1 increased. The Results likewise report that GAP43 mRNA did not increase in the CARM1-depleted cell line examined. Thus the claim is correct about tau and p27 but contrary to the paper on GAP43 mRNA. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  cites Fujiwara et al. 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Hubers et al. 2010 source

In the paper

“The HuD protein, like all Hu members, has a molecular weight of ∼40 kDa and contains three RNA recognition motifs (RRMs) with a linker region separating the second and third RRM (Fig. 1C; Good 1995; Liu et al. 1995; Okano and Darnell 1997).”

What the sources say

• ?Not checked — no full text of the sourcecites Good 1995 source
• ?Not checked — no full text of the sourcecites Liu et al. 1995 source
• Supported

  The Abstract describes HuD as encoding a target antigen among antigens of 35–40 kDa and states that Hu antigens have three RNA recognition motifs. The Cloning of mouse Hu gene family members section identifies a spacer region between RRM 2 and RRM 3. Page numbers are not provided in our copy. (LLM, conf=0.89)

  cites Okano and Darnell 1997 source

In the paper

“Nevertheless, there are a few known AUBPs that enhance mRNA stability, with Hu proteins being the most notable (Brennan and Steitz 2001; Hinman and Lou 2008; Pascale et al. 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Brennan and Steitz 2001 source
• Supported

  In “Hu proteins and mRNA stability,” the paper says that most ARE-binding proteins decrease mRNA stability, whereas Hu proteins stabilize their target mRNAs. It also describes regulation of mRNA stability as the most well-known molecular function of Hu proteins, supporting the citing sentence’s characterization. (LLM, conf=0.91)

  cites Hinman and Lou 2008 source
• ?Not checked — no full text of the sourcecites Pascale et al. 2008 source

In the paper

“ARE motifs are typically found in short-lived transcripts encoding proteins with diverse functions such as cellular proliferation, differentiation, transcription, RNA metabolism, inflammation, and stress-response (Bakheet et al. 2006; Khabar 2010).”

What the sources say

• ?Not matched

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

  cites Bakheet et al. 2006
• Supported

  The Introduction describes ARE-bearing mRNAs as functionally diverse, listing proliferation, transcription, RNA metabolism, inflammatory responses, and development, and links these genes to rapid mRNA decay. It also identifies ARE-mediated regulation in external stress-mediated pathways; the sequence-characteristics section says ARE motifs occur preferentially in labile transcripts. The claim is a fair broad paraphrase, with differentiation corresponding to the paper’s broader category of development. (LLM, conf=0.88)

  cites Khabar 2010 source

In the paper

“Out of the roughly 20 currently known AUBPs, the majority are expressed in neurons and promote mRNA decay including, for example, AUF1, TTP, and KSRP (Table 1; Wu and Brewer 2012).”

What the sources say

• Partly supported

  Section 4.1 says there are about 20 known AUBPs, that most recruit mRNA-degradation machinery, and that AUF1, TTP, and KSRP promote degradation. It does not establish that a majority of AUBPs are expressed in neurons. (LLM, conf=0.90)

  cites Wu and Brewer 2012 sourceExperimental — accuracy not yet measured

In the paper

“In developing neurons, HuD is found in growth cones of extending neurites, while in mature neurons it is present in axons and dendrites, including at the pre- and post-neurite terminals, respectively (Aranda-Abreu et al. 1999; Aronov et al. 2002).”

What the sources say

• Partly supported

  The Results section, “The ELAV-like protein–tau mRNA complex is associated with microtubules in vivo” (page not provided), reports ELAV-like protein staining extending into neurites and growth cones of NGF-treated PC12 cells. It does not establish that the staining is specifically HuD, or describe HuD in the axons, dendrites, or pre- and post-neurite terminals of mature neurons. (LLM, conf=0.85)

  cites Aranda-Abreu et al. 1999 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Aronov et al. 2002 source

In the paper

“Since the 6.0-kb variant is less stable and not as efficiently translated as the 2.4-kb transcript, the authors postulated that the reduction of HuR expression prevents HuR’s ability to promote proliferation and thereby permits neurons to terminally differentiate (Mansfield and Keene 2011).”

What the sources say

• Supported

  The Results sections on mRNA stability and translation (page not supplied) report that the 6.0-kb isoform is much less stable than the 2.4-kb isoform and that its 3′-UTR produces significantly less reporter expression. The Discussion explicitly presents reduced HuR expression permitting neuronal differentiation as a hypothesis, as the citing sentence does. (LLM, conf=0.91)

  cites Mansfield and Keene 2011 source

In the paper

“The initial demonstration that Hu proteins regulate mRNA stability was based on the observation that HuB enhances GLUT1 mRNA half-life and, incidentally, translation (Jain et al. 1997).”

What the sources say

• Supported

  In the Results section (page not provided), GLUT1 mRNA half-life rose from 4.8 hours in untransfected cells to 7.0 hours in Hel-N1-expressing cells. The Discussion (page not provided) reports a Hel-N1-associated increase in GLUT1 translation, based on polysome profiles. The paper uses the name Hel-N1 rather than HuB. (LLM, conf=0.89)

  cites Jain et al. 1997 source

In the paper

“In line with previous studies, nELAVs were found to enhance exon inclusion when bound to 5′ SSs in the downstream intron and inhibit exon inclusion when bound to adjacent 3′ and 5′ SSs of alternative exons.”

What the sources say

• Supported

  The Results section, “Generation of nElavl-RNA regulatory map” (page not provided), reports preferential binding at the downstream intron’s 5′ splice site where nElavl promotes inclusion, and at the immediate 3′ and 5′ splice sites where it promotes exclusion. (LLM, conf=0.95)

  cites Ince-Dunn et al. 2012 source

In the paper

“Interestingly, HuD is more effective at stabilizing GAP-43 mRNAs that contain a longer poly(A) tail, indicating that HuD binds to both the ARE and poly(A) tail to increase GAP-43 mRNA half-life (Beckel-Mitchener et al. 2002).”

What the sources say

• Partly supported

  The Results report that HuD preferentially stabilizes GAP-43 mRNA with long poly(A) tails and increases its half-life. The Discussion says HuD binding to the ARE was measured, but binding to the poly(A) tail was only a possible explanation consistent with the data—not a demonstrated mechanism. Page numbers are not provided in our copy. (LLM, conf=0.88)

  cites Beckel-Mitchener et al. 2002 sourceExperimental — accuracy not yet measured

In the paper

“In addition to these transcripts, HuD has been shown to bind and regulate several other mRNAs in vitro and in vivo, many of which encode proteins with important functions in neuronal differentiation such as cell cycle arrest (p21cip1/waf1) (Joseph et al. 1998), neuroblast proliferation (MSI-1) (Ratti et al. 2006), neuron migration (MARCKS) (Wein et al. 2003), neurite extension ([GAP-43] [Chung et”

What the sources say

• ?Not checked — no full text of the sourcecites Joseph et al. 1998 source
• ?Could not verify

  The indexed copy contains a repository title indicating ELAV-related stabilization of Msi1 mRNA, but no article passage establishing that HuD binds or regulates it, or linking MSI-1 to neuroblast proliferation. Searches for HuD and Msi1 regulation returned only repository metadata and a PDF listing, not the paper’s substantive text. The other listed transcripts are attributed to separate citations in the citing sentence. (LLM, conf=0.72)

  cites Ratti et al. 2006 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Wein et al. 2003

In the paper

“Multiple studies have shown that overexpression or down-regulation of HuD results in increased or decreased, respectively, GAP-43 mRNA levels and/or stability in cultured cells and the mouse nervous system (Anderson et al. 2000, 2001; Mobarak et al. 2000; Bolognani et al. 2006, 2007a).”

What the sources say

• ?Not matched

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

  cites Anderson et al. 2000, 2001
• Supported

  The Results report that HuD overexpression increased GAP-43 mRNA levels and extended its half-life from 5 to 9 hours in PC12 cells; HuD down-regulation shortened the half-life. This supports the cultured-cell portion for which this paper is cited. The sentence cites multiple studies for the broader statement about the mouse nervous system. (LLM, conf=0.92)

  cites Mobarak et al. 2000 source
• ?Not matched

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

  cites Bolognani et al. 2006, 2007a

In the paper

“In addition, a recent report identified intronic nELAV binding sites flanking an alternative 3′ SS in the Gls1/Gls gene and demonstrated that nELAVs generate a longer Gls mRNA variant, indicating that they may enhance inclusion of a Gls 3′ exon(s) (Ince-Dunn et al. 2012).”

What the sources say

• Supported

  The Results section (‘A new role for nElavl in regulating glutamate in the brain,’ Fig. 6) reports intronic nElavl binding sites flanking the alternative Gls1 splice site and suggests that nElavl promotes use of the longer Gls1-l isoform. It also reports that Gls1-l mRNA falls to about 50% of wild-type levels when Elavl3 and Elavl4 are knocked out, supporting the citing sentence’s hedged interpretation. (LLM, conf=0.90)

  cites Ince-Dunn et al. 2012 source

In the paper

“Employing mainly REMSAs and in vitro cleavage and polyadenylation assays, one study determined that Hu proteins bind U-rich sequences downstream from the exon 4 poly(A) signal in calcitonin/CGRP to block binding of cleavage stimulation factor 64 (CstF64) and cleavage-polyadenylation specificity factor (CPSF), essential components of the cleavage and polyadenylation machinery. Through this”

What the sources say

• Partly supported

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

  cites Zhu et al. 2006 sourceExperimental — accuracy not yet measured

In the paper

“In addition to GAP-43 transcripts, HuD has also been shown to promote the stability of several other ARE-containing mRNAs in neurons, such as AChE (Deschenes-Furry et al. 2003) and Nova1 (Ratti et al. 2008), both in vitro and in vivo (Table 2; Perrone-Bizzozero and Bird 2013).”

What the sources say

• Supported

  Deschênes-Furry et al. is cited for the AChE portion of the sentence; Nova1 and the broader in-vitro/in-vivo statement have separate citations. In the Discussion (page unavailable), the paper reports that AChE transcript abundance varied with HuD expression in PC12 cells and that HuD increased expression through the AChE 3′-UTR, supporting the attributed post-transcriptional effect. (LLM, conf=0.85)

  cites Deschenes-Furry et al. 2003 source
• Partly supported

  The Nova1 mRNA degradation results (page unavailable) show that HuD re-expression prolonged Nova1 mRNA half-life in cultured NSC34 cells, supporting the Nova1 stability claim in cells. The Experimental Procedures identify NSC34 as a cell line; this paper does not establish Nova1 mRNA stabilization in an organism. AChE is attributed to a different citation in the citing sentence and is not judged here. (LLM, conf=0.88)

  cites Ratti et al. 2008 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Perrone-Bizzozero and Bird 2013

In the paper

“Of particular interest, this study also found that HuD binds mRNAs of several RBPs, including its own, HuB, HuR, Cugbp2, Musashi 2, and Staufen 2, indicating a complex regulatory network between HuD and other components of the ribonome (Pullmann et al. 2007; Mansfield and Keene 2009; Bolognani et al. 2010).”

What the sources say

• ?Could not verify

  The Abstract (page unavailable) says the study investigated AUF1, HuR, KSRP, NF90, TIA-1, and TIAR, and found binding among some of their mRNAs. Neither it nor the additional passages retrieved for HuD, Cugbp2, Musashi 2, and Staufen 2 reports the claimed HuD binding relationships. (LLM, conf=0.76)

  cites Pullmann et al. 2007 sourceExperimental — accuracy not yet measured
• Partly supported

  The “Regulators of regulators” section (page unavailable) describes RBPs binding their own and one another’s mRNAs, supporting the idea of an interconnected ribonome. It discusses a group including HuR, not HuD; our copy does not report HuD binding the listed mRNAs (searched: HuD, Cugbp2, Musashi, Staufen). (LLM, conf=0.82)

  cites Mansfield and Keene 2009 sourceExperimental — accuracy not yet measured
• Supported

  The Discussion lists HuD itself, HuB, HuR, Cugbp2, Musashi 2, and Staufen 2 among the RBP mRNAs identified as HuD targets. It also says these observations support a complex, integrated network of post-transcriptional regulators. (LLM, conf=0.94)

  cites Bolognani et al. 2010 source

In the paper

“Using a variety of complementary techniques, including an in vitro protein methylation assay, CARM1 was demonstrated to interact with and methylate an amino acid located in the hinge region of rat (Arg236) (Fujiwara et al. 2006) and mouse (Arg248) (Hubers et al. 2010) HuD (Fig. 1C).”

What the sources say

• Supported

  The Results identify HuD Arg236 as a CARM1 methylation target, and the Discussion locates Arg236 in the hinge region. The Results also show CARM1 and HuD colocalizing in PC12 cells. The mouse Arg248 statement is attached to a different citation, not Fujiwara et al. (LLM, conf=0.90)

  cites Fujiwara et al. 2006 source
• ?Not checked — no full text of the sourcecites Hubers et al. 2010 source

In the paper

“On the other hand, inhibition of HuD methylation or knockdown of CARM1 resulted in increased p21cip1/waf1 mRNA levels, cell-cycle withdrawal, and neuronal differentiation.”

What the sources say

• Partly supported

  The Results report a 3.26-fold increase in p21cip1/waf1 mRNA in a CARM1-depleted PC12 clone, and slower proliferation and greater neurite outgrowth in depleted clones. The Discussion describes partially differentiated cells, while the Results show accelerated neuritogenesis mainly in response to NGF. The paper does not establish cell-cycle withdrawal: slower proliferation is not the same as cell-cycle exit. (LLM, conf=0.84)

  cites Fujiwara et al. 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Hubers et al. 2010 source

In the paper

“The classical PKCα isoform was shown to increase nELAV levels and provoke their nuclear export following treatment of SH-SY5Y NB cells with the PKC-activating compounds phorbol esters and bryostatin-1 (Pascale et al. 2005).”

What the sources say

• Supported

  The Results report that PMA and bryostatin-1 treatment of SH-SY5Y cells reduced nuclear nELAV staining and increased total nELAV protein levels. The PKCα knock-down and inhibition experiments identify PKCα as mediating the PMA-induced increase; the Discussion places nuclear export and up-regulation in the PKCα-involving pathway. (LLM, conf=0.90)

  cites Pascale et al. 2005 source

In the paper

“Moreover, stimulation of PKCα promotes its interaction with nELAV proteins resulting in their phosphorylation at threonine residues, redistribution to the neuronal cytoskeletal and membrane fractions, and stabilization of GAP-43 mRNA.”

What the sources say

• Partly supported

  The Results report that PKC activation increases PKCα’s association with nELAV proteins and nELAV threonine phosphorylation; they also show PKCα-dependent stabilization of GAP-43 mRNA. However, the Results say the increase in nELAV proteins is confined to the cytoskeletal compartment. It is PKCα, not nELAV, that translocates to both membrane and cytoskeletal fractions (page unavailable in our copy). (LLM, conf=0.89)

  cites Pascale et al. 2005 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, methylation of HuD decreased p21cip1/waf1 mRNA stability and maintained neuronal precursor cells in a proliferative state.”

What the sources say

• Partly supported

  The Results report that reducing HuD methylation lengthened p21cip1/waf1 mRNA half-life in PC12 cells, and the Abstract suggests that methylated HuD maintains those cells in a proliferative state by promoting mRNA decay. The claim extends this finding from PC12 cells to neuronal precursor cells generally, which the cited paper does not establish. (LLM, conf=0.86)

  cites Fujiwara et al. 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Hubers et al. 2010 source

In the paper

“Importantly, HuD is a focal downstream target of this neurite-extending pathway since nerve growth factor (NGF) or phorbol ester treatment of PC12 cells following HuD knockdown prevents neurite outgrowth (Mobarak et al. 2000).”

What the sources say

• Supported

  The Results report that PC12 cells with reduced HuD did not show increased neurite outgrowth after NGF treatment and that phorbol ester failed to induce neurite outgrowth, producing only short, stubby processes. The Discussion describes HuD reduction as selectively affecting the pathway activated by NGF and phorbol esters, while leaving the response to cAMP intact. The claim concerns outgrowth through that pathway, not all neurite outgrowth. (LLM, conf=0.91)

  cites Mobarak et al. 2000 source

In the paper

“The report by Kullman et al. suggests that inhibition of p27 translation by Hu proteins is an event that sustains cells in a proliferative state (Kullmann et al. 2002).”

What the sources say

• Supported

  The Results (Fig. 7) report that HuR knockdown increased the proportion of G1-phase cells and reduced the S-phase proportion. The authors conclude that HuR helps regulate proliferation in part by inhibiting p27 translation, supporting the citing sentence’s qualified interpretation. (LLM, conf=0.92)

  cites Kullmann et al. 2002 source

In the paper

“Even though the mechanism of translational silencing is unclear, it was demonstrated to require HuD binding to an internal ribosome entry site (IRES) in the 5′ UTR of p27 mRNA (Kullmann et al. 2002) and a short ∼22-nt sequence in the 5′ UTR of Ins2 mRNA (Lee et al. 2012).”

What the sources say

• Partly supported

  The Results (page not provided) show that HuD binds specifically to the p27 5′ UTR and that HuD overexpression inhibits p27 translation and IRES activity. They do not establish that HuD binds the IRES itself or that such binding is required for silencing. The Ins2 sequence is attributed to Lee et al. (2012), not to Kullmann et al. (LLM, conf=0.86)

  cites Kullmann et al. 2002 sourceExperimental — accuracy not yet measured
• Supported

  The Lee et al. citation supports the Ins2 portion of the sentence, not the separately cited p27 portion. In the Results section, the paper identifies positions 52–73 of the Ins2 5′ UTR as a HuD-binding segment and reports that this segment confers HuD-dependent repression in a translation reporter assay. Page numbers are not provided in our copy. (LLM, conf=0.92)

  cites Lee et al. 2012 source

In the paper

“Various conditions, including KCl depolarization of primary hippocampal neurons, cocaine, or seizure treatment of mice and phorbol ester or bryostatin-1 application to human neuroblastoma (NB) cells, result in an augmented abundance of HuD, its redistribution to neurites, and its increased association with mRNAs and mRNP components (Pascale et al. 2005; Tiruchinapalli et al. 2008a,b).”

What the sources say

• Partly supported

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

  cites Pascale et al. 2005 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Tiruchinapalli et al. 2008a,b

In the paper

“One functional consequence of this auto-regulatory binding is presumably in controlling alternative splicing of its own pre-mRNA (see above) (Wang et al. 2010).”

What the sources say

• Supported

  The Discussion (‘A novel enhancer function of Hu proteins in splicing regulation’) states that Hu proteins bind intronic sequences to promote inclusion of HuD exon 6. Another Discussion passage (‘Biological function of alternative inclusion of HuD exon 6’) identifies HuD itself among the isoforms that promote that inclusion, supporting the citing sentence’s hedged description of autoregulation. (LLM, conf=0.90)

  cites Wang et al. 2010 source

In the paper

“Prior to our study, only two transcriptional mechanisms were known to regulate expression of the HuD gene—thyroid hormone (T3; presumably via activation of the thyroid hormone receptor) and TF forkhead box O1 (FoxO1)—and both of these factors were shown to negatively impact the abundance of HuD.”

What the sources say

• Partly supported

  In “HuD gene transcription is repressed by T3” (page not available), run-on assays show that T3 reduced HuD transcription by 60%; the paper also reports reduced HuD RNA in cells with appropriate thyroid hormone receptor levels. Our copy does not address FoxO1 or establish that these were the only two known transcriptional mechanisms. (LLM, conf=0.88)

  cites Cuadrado et al. 2003 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (‘HuD is expressed in pancreatic β cells’; page not provided) shows that FoxO1 binds the HuD promoter and that FoxO1 overexpression reduces HuD, supporting its role as a negative transcriptional regulator. The passages found do not address thyroid hormone (T3) or establish that these were the only two known transcriptional mechanisms. (LLM, conf=0.88)

  cites Lee et al. 2012 sourceExperimental — accuracy not yet measured

In the paper

“For example, neurosphere assays using neuronal stem/progenitor cells from the cerebral cortex of HuD knockout (−/−) mice revealed that HuD decreases self-renewal capacity and promotes cell cycle exit and differentiation of these cells.”

What the sources say

• Partly supported

  The Results report that neurospheres from HuD-knockout embryonic cerebral cortex showed increased self-renewal, while a neurosphere differentiation assay found reduced production of neuronal progeny. The paper also concludes that HuD promotes cell-cycle exit, but that finding came from labeling experiments in the embryonic cerebral wall, not the neurosphere assays. No page numbers are available in our copy. (LLM, conf=0.86)

  cites Akamatsu et al. 2005 sourceExperimental — accuracy not yet measured

In the paper

“T3 was demonstrated to decrease HuD mRNA synthesis in neuronal N2a cells, and T3 levels were inversely correlated with HuD mRNA levels in the rat brain (Cuadrado et al. 2003)”

What the sources say

• Partly supported

  The section ‘T3 inhibits HuD expression in PC12 and N2a cells’ reports reduced HuD RNA expression in N2a cells, while ‘HuD gene transcription is repressed by T3’ reports a reduced transcription rate without establishing that result specifically in N2a cells. The rat-brain results show higher HuD RNA under thyroid deficiency only in certain regions of the developing brain; they do not report a measured correlation between T3 and HuD mRNA levels across the rat brain. (LLM, conf=0.86)

  cites Cuadrado et al. 2003 sourceExperimental — accuracy not yet measured

In the paper

“Detailed analysis of these mice showed enhanced sprouting of GAP-43-containing mossy fibers to the CA3 region, ectopic expression of GAP-43 protein in the DG, and increased GAP-43 and calmodulin binding, possibly causing altered calcium signalling (Tanner et al. 2008).”

What the sources say

• Partly supported

  The Results report GAP-43-positive mossy fibers in CA3, increased GAP-43 staining in the dentate gyrus, and increased calmodulin binding to GAP-43; the Conclusions propose that calmodulin sequestration may alter calcium signaling (pages unavailable). But the Results do not establish enhanced mossy-fiber sprouting: the authors say the fibers interpreted as possible sprouts could instead have other origins. (LLM, conf=0.88)

  cites Tanner et al. 2008 sourceExperimental — accuracy not yet measured

In the paper

“In adult HuD−/− mice, an abnormal clasping reflex and poor performance on the rotarod test were observed, suggesting a sensory/motor defect in these animals and a role for HuD at the axon terminal (Akamatsu et al. 2005).”

What the sources say

• Supported

  The Results report that 70–80% of HuD−/− mice showed an abnormal hind-limb clasping reflex by 4–8 weeks of age. The same section reports that adult HuD−/− mice stayed on the rotarod for significantly less time than wild-type mice and continued to perform poorly across trials. (LLM, conf=0.94)

  cites Akamatsu et al. 2005 source

In the paper

“This function of HuD requires its shuttling to the cytoplasm and involves stabilization of various target mRNAs whose protein products promote microtubule assembly and growth cone development including GAP-43, Tau, and AChE (Chung et al. 1997; Aranda-Abreu et al. 1999; Kasashima et al. 1999; Deschenes-Furry et al. 2003).”

What the sources say

• Partly supported

  The GAP-43 binding-site results show that HuD binds a conserved element in GAP-43 mRNA. The Discussion proposes a possible role for Elav-like proteins in GAP-43 regulation, but treats their involvement in mRNA stabilization as a hypothesis requiring further investigation. This paper does not establish that HuD must shuttle to the cytoplasm or that it stabilizes the listed target mRNAs. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites Chung et al. 1997 sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘Characterization of HuD–tau mRNA complex formation’ section shows that HuD binds tau mRNA, and the antisense-treatment results link reduced HuD to reduced tau mRNA and protein in PC12 cells. The Discussion treats tau mRNA stabilization as a possible mechanism but says how ELAV-like proteins control mRNA half-life remains undetermined. These passages do not establish that HuD must shuttle to the cytoplasm or that this paper demonstrates stabilization of GAP-43 and AChE mRNAs. Page numbers were unavailable in the indexed passages. (LLM, conf=0.86)

  cites Aranda-Abreu et al. 1999 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Kasashima et al. 1999 source

In the paper

“suggesting a sensory/motor defect in these animals and a role for HuD at the axon terminal (Akamatsu et al. 2005).”

What the sources say

• Partly supported

  The Results (page unavailable) report abnormal hind-limb clasping in adult HuD−/− mice, describe it as indicating motor/sensory defects, and report significantly poorer rotarod performance than in wild-type mice. Our copy does not connect these findings to a role for HuD at the axon terminal. (LLM, conf=0.86)

  cites Akamatsu et al. 2005 sourceExperimental — accuracy not yet measured

In the paper

“A study in our laboratory demonstrated that, between 1 and 4 d following axotomy of superior cervical ganglion (SCG) neurons, HuD protein and mRNA levels, its interaction with AChE mRNA, and AChE transcript levels decreased (Deschenes-Furry et al. 2007).”

What the sources say

• Supported

  In “HuD expression is altered after SCG axotomy,” HuD transcripts decreased within 1 day and remained low through day 4; HuD protein was also reduced at day 2. “Axotomy alters AChE mRNA and protein interactions” reports reduced HuD binding to AChE RNA after axotomy, while “Axonal injury results in decreased AChE mRNA levels” reports declining AChE transcripts at days 1, 2, and 4. (LLM, conf=0.93)

  cites Deschenes-Furry et al. 2007 source

In the paper

“In the hippocampus of AD patients, nELAV protein abundance was found to decrease in parallel with clinical dementia progression, and their expression was inversely correlated with Aβ peptide levels both in vitro and in vivo (Amadio et al. 2009).”

What the sources say

• Partly supported

  The Results section, “The nELAV are decreased in postmortem AD patients” (page unavailable), reports that hippocampal nELAV levels fell with dementia progression and were inversely correlated with hippocampal Aβ content. The Results section, “Aβ intracellular accumulation induces a reduction of nELAV in SH-SY5Y cells” (page unavailable), reports that Aβ exposure reduced nELAV in vitro, but does not establish an inverse correlation between their measured levels in vitro. (LLM, conf=0.86)

  cites Amadio et al. 2009 sourceExperimental — accuracy not yet measured

In the paper

“Recent findings in our laboratory, however, have identified the expression of five additional HuD E1 variants, resulting in a total of eight (Fig. 1A,B; Bronicki et al. 2012).”

What the sources say

• ?Not matched

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

  cites Bronicki et al. 2012

In the paper

“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.”

What the sources say

• ?Not matched

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

  cites Bronicki et al. 2012

In the paper

“As mentioned above, previous studies, along with data from our laboratory, revealed eight HuD E1 variants, indicating the existence of at least eight different 5′ UTRs (Fig. 1A,B), with most containing an in-frame translation start site (Abe et al. 1994; Inman et al. 1998; Bronicki et al. 2012).”

What the sources say

• ?Not matched

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

  cites Abe et al. 1994
• ?Not checked — no full text of the sourcecites Inman et al. 1998 source
• ?Not matched

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

  cites Bronicki et al. 2012

In the paper

“Remarkably, E1 and E′1 partially align with mouse E1b and E1c, respectively (L Bronicki and BJ Jasmin, unpubl.), implying that the developmental regulation and function of these two mammalian exons is evolutionarily conserved.”

What the sources say

• ?Not matched

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

  cites L Bronicki and BJ Jasmin, unpubl.

In the paper

“RT-PCR analysis revealed that all eight exons are expressed in embryonic and adult mouse brain and are induced during neuronal differentiation.”

In the paper

“Additionally, we demonstrated that a highly conserved 400-bp region upstream of the predominantly expressed E1 variant, E1c, houses several E-boxes, two of which are targeted by the basic helix-loop-helix transcription factor Neurogenin 2 (Ngn2).”

In the paper

“HuD is an RNA-binding protein that has been implicated in a wide variety of regulatory processes involving mRNA metabolism in neurons.”

In the paper

“In the HuD gene locus, E2 and E3, E4 and E5, and E8 encode the three RRMs, respectively, whereas the alternatively spliced E6 and E7 encode the linker region (Inman et al. 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Inman et al. 1998 source

In the paper

“Overall, the HuD gene is well conserved among higher vertebrates and is located on chromosome 1 in humans and chromosome 4 in mice (Fig. 1A).”

What the sources say

• ?Not matched

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

  cites Sekido et al. 1994
• ?Not checked — no full text of the sourcecites Inman et al. 1998 source

In the paper

“The human and mouse HuD gene spans ∼146 kb of DNA and is divided into seven coding exons (E2 to E8) that encompass ∼44 kb of DNA (Sekido et al. 1994; Inman et al. 1998).”

What the sources say

• ?Not matched

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

  cites Sekido et al. 1994
• ?Not checked — no full text of the sourcecites Inman et al. 1998 source

In the paper

“The HuD linker region contains multiple residues that are post-translationally modified and houses the nuclear export (NES) and putative nuclear localization (NLS) signals (Kasashima et al. 1999).”

What the sources say

• ?Not checked — no full text of the sourcecites Kasashima et al. 1999 source

In the paper

“In addition to the 5′ end, HuD pre-mRNA is subjected to alternative splicing of exons (E) 6 and 7, resulting in three additional transcript isoforms (HuD, HuDmex, and HuDpro) (Fig. 1B,C), two of which are predominantly expressed in the postnatal mouse brain (HuD and HuDpro) (Inman et al. 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Inman et al. 1998 source

In the paper

“AREs usually range from 50 to 150 nt in size and, as their name indicates, consist of A- and U-rich stretches.”

In the paper

“However, it is important to point out that the presence of an AUUUA sequence is not always sufficient for HuD binding, indicating that HuD displays preference for specific ARE motifs (Toba et al. 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites Toba et al. 2002 source

In the paper

“Multiple laboratories have demonstrated via Northern blots and quantitative RT-PCR that HuD mRNA levels are detectable by day 10 of mouse and rat embryonic brain development, peak at E16, and slowly decline until birth (Clayton et al. 1998; Hambardzumyan et al. 2009; Abdelmohsen et al. 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Clayton et al. 1998 source
• ?Not matched

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

  cites Hambardzumyan et al. 2009
• ?Not checked — no full text of the sourcecites Abdelmohsen et al. 2010 source

In the paper

“The first motif consists of C- and U-rich stretches, with a prevalence of the former, and is located mostly in the 5′ and 3′ UTRs of mRNAs.”

What the sources say

• ?Not matched

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

  cites Bolognani et al. 2010

In the paper

“The most extensively studied HuD-targeted cis-acting elements are adenosine/uridine (A/U)-rich elements (AREs) commonly found in the 3′ UTR of almost 10% of cellular mRNAs (Halees et al. 2008).”

What the sources say

• ?Not matched

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

  cites Halees et al. 2008

In the paper

“Deletion and mutational analysis of the HuD protein revealed that the first two RRMs bind to the cis-acting elements, typically in the 3′ UTR, while the third RRM interacts with the poly(A) tail of transcripts and stabilizes the RBP-mRNA complex (Chung et al. 1996, 1997; Ma et al. 1997; Ross et al. 1997; Anderson et al. 2000; Park et al. 2000; Wang and Tanaka Hall 2001; Beckel-Mitchener et al. 200”

What the sources say

• ?Not matched

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

  cites Chung et al. 1996, 1997
• ?Not matched

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

  cites Ma et al. 1997
• ?Not checked — no full text of the sourcecites Ross et al. 1997 source

In the paper

“These motifs vary considerably in sequence, and for simplification, they are categorized into three major classes; class I contains one to three AUUUA pentamers in a U-rich context, class II includes overlapping UUAUUUAUU nonamers, and class III consists of U-rich sequences without AUUUA pentamers (Bakheet et al. 2003, 2006).”

What the sources say

• ?Not matched

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

  cites Bakheet et al. 2003, 2006

In the paper

“The second and third motifs are U-rich with interspersed guanines (G) or adenosines (A), respectively. These latter two motifs are predominantly found in the 3′ UTR and occasionally in the 5′ UTR and coding regions of mRNAs.”

What the sources say

• ?Not matched

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

  cites Bolognani et al. 2010

In the paper

“Moreover, in vitro binding assays showed that the first two RRMs of HuD associate with the primary general mRNA export adaptor complex (TAP-p15; also known as NXF1/NXT1) in a RNA-independent manner and that this interaction may be necessary for shuttling of HuD (Saito et al. 2004).”

What the sources say

• ?Not checked — no full text of the sourcecites Saito et al. 2004 source

In the paper

“These results indicate that AKT1 increases the abundance of HuD protein and interacts with the HuD-mRNA complex to promote neurite elongation, possibly through regulation of HuD-mediated translation.”

In the paper

“Based on these findings, an emerging model suggests that, through post-translational control of HuD expression and function, activation of different signalling pathways can maintain neuronal precursor/stem cells in a proliferative state (CARM1) or promote neuronal differentiation (PKC and AKT1) (Fig. 4A).”

In the paper

“Altogether, these studies indicate that HuD recruits mRNAs to microtubules and may transport them to neurites to control their local translation in response to extracellular cues, particularly during neuronal development and function.”

In the paper

“The mammalian HuD mRNA contains at least three alternate 5′ UTRs and a long 3′ UTR (∼2.6 kb), characteristics that are a strong indication of predisposition to post-transcriptional regulation.”

In the paper

“In the study by Fujiwara et al., HuD mutants were used to demonstrate direct binding of active (phosphorylated) AKT1 to a sequence in the linker region of HuD and that this interaction is required for HuD-dependent neurite outgrowth (Fujiwara et al. 2011a).”

What the sources say

• ?Not matched

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

  cites Fujiwara et al. 2011a

In the paper

“In addition, a recent study demonstrated that PKCε also interacts with HuD, and activation of both PKC isoforms by bryostatin-1 results in HuD phosphorylation on nine residues (Lim and Alkon 2012).”

What the sources say

• ?Not checked — no full text of the sourcecites Lim and Alkon 2012 source

In the paper

“HuD pre-mRNA undergoes alternative splicing, including inclusion of E6 mediated by Hu proteins.”

In the paper

“CARM1 methylation of HuD prevents its binding to specific mRNA targets and maintains neuronal precursors in an undifferentiated state.”

In the paper

“Further support of the notion that trans-acting factors regulate HuD mRNA metabolism surfaced when miR-375 was demonstrated to target the 3′ UTR of HuD and decrease its abundance by reducing both its mRNA stability and translation (Abdelmohsen et al. 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Abdelmohsen et al. 2010 source

In the paper

“adding to the speculation that multiple promoters control HuD expression”

In the paper

“Another possible significance of this interaction may be similar to the one found for the Drosophila ELAV homolog, which was demonstrated to negatively regulate its own transcript (Samson 1998; Borgeson and Samson 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Samson 1998 source
• ?Not matched

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

  cites Borgeson and Samson 2005

In the paper

“implying that this fragment encompasses an important evolutionarily conserved regulatory structure and/or cis-element(s)”

In the paper

“On the other hand, an increase in unmethylated HuD protein levels, its post-translational modification (such as phosphorylation by PKC isoforms), and interaction with other proteins (e.g., AKT1) enable HuD to regulate mRNA metabolism of proneural genes and promote neuronal differentiation/neurite extension.”

In the paper

“As discussed above, a previous study suggested that at least three HuD E1 variants exist, pointing to the potential presence of multiple promoters (Inman et al. 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Inman et al. 1998 source

In the paper

“Synthesis of HuD mRNA is negatively regulated by thyroid hormone (presumably bound to thyroid hormone receptor) in neurons and FoxO1 in pancreatic β cells.”

In the paper

“These studies suggest that the decrease in nELAV protein levels leads to reduced ADAM10 expression which may be an important event in the development of AD.”

In the paper

“these studies indicate that HuD is important for various types of neuronal plasticity, potentially by directly acting at the synapse.”

In the paper

“Although these mice displayed physiological and molecular alterations including ectopic HuD protein expression throughout the hippocampus, they exhibited aberrant acquisition and retention of memories possibly due to the lack of strict temporal and spatial regulation of HuD protein (Bolognani et al. 2007b).”

What the sources say

• ?Not matched

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

  cites Bolognani et al. 2007b

In the paper

“A second study analyzed five SNPs in the HuD locus from Norwegian, United States, and Irish PD and control samples and found that two SNPs (rs967582 and rs3902720) are associated with AAO of PD but only in Irish patient samples, possibly due to a Celtic founder effect (Haugarvoll et al. 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Haugarvoll et al. 2007 source

In the paper

“Moreover, glutamate receptor activation following cocaine treatment was shown to increase HuD protein and target mRNA abundance (e.g., GAP-43) and promote HuD localization to dendritic spines (Tiruchinapalli et al. 2008a).”

What the sources say

• ?Not matched

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

  cites Tiruchinapalli et al. 2008a

In the paper

“In addition to this function, increasing evidence implicates HuD in neuronal plasticity, nerve injury, learning and memory, and multiple neuronal diseases.”

In the paper

“since the HuD gene may contain multiple promoters”

In the paper

“indicating that increased levels of HuD in brains of schizophrenic patients may lead to altered post-transcriptional control and, consequently, an abundance of various HuD-targeted mRNA products (Perrone-Bizzozero and Bird 2013).”

What the sources say

• ?Not matched

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

  cites Perrone-Bizzozero and Bird 2013

In the paper

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

In the paper

“In these cells, haploinsufficiency of HuD is thought to promote amplification of the N-myc gene and result in poor patient outcome (Grandinetti et al. 2006).”

What the sources say

• ?Not matched

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

  cites Grandinetti et al. 2006

In the paper

“and harbors eight exon 1 variants and an extensive 3′ UTR.”

In the paper

“In line with this, a recent study screened various neuroendocrine lung tumors and found 11 mutations of unidentified consequence(s) and two mutations that prevent full-length protein expression in the HuD gene (D’Alessandro et al. 2010).”

What the sources say

• ?Not matched

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

  cites D’Alessandro et al. 2010