Cytoplasmic localization is required for the mammalian ELAV‐like protein HuD to induce neuronal differentiation

Kasashima, Katsumi; Terashima, Kazuhiro; Yamamoto, Kōichi; Sakashita, Eiji; Sakamoto, Hiroshi

doi:10.1046/j.1365-2443.1999.00292.x

Cited by 110 publications

(116 citation statements)

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“…1C) and CA1 hippocampal (not shown) subfields. This pattern of distribution is reminiscent of that observed in PC12 cells, in which a strong neurite-inducing activity is strictly dependent on cytoplasmic localization of overexpressed HuD (8). To better identify the cell compartments of maximal ELAV-like protein increase, we examined different cellular fractions obtained from AC and TR mice hippocampi.…”

Section: Resultsmentioning

confidence: 79%

“…As elav is necessary for the development and maintenance of the fly nervous system (5), the ELAV-like HuB, HuC, and HuD genes (expressed only in neurons, whereas HuA, also called HuR, is ubiquitous) are early markers of neuronal differentiation (6) and appear to be necessary to accomplish this cellular program (7,8). All four members of this family code for RNA-binding proteins endowed with three RNA-interacting domains of the RRM type (4).…”

mentioning

confidence: 99%

“…The neuron-specific expression of HuB, HuC, and HuD; their demonstrated nucleocytoplasmic shuttling capability (15); their clear neurite-inducing activity (8); and their positive regulation of an array of target genes all make them very attractive candidates for a role in memory. In this work we clearly demonstrate such a role for two spatial learning paradigms in rodents, at the same time providing evidence for the involvement of posttranscriptional events in the learning-induced reprogramming of gene expression.…”

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confidence: 99%

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Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

Quattrone

Pascale

Nogués

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

130

125

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The view that memory is encoded by variations in the strength of synapses implies that long-term biochemical changes take place within subcellular microdomains of neurons. These changes are thought ultimately to be an effect of transcriptional regulation of specific genes. Localized changes, however, cannot be fully explained by a purely transcriptional control of gene expression. The neuron-specific ELAV-like HuB, HuC, and HuD RNA-binding proteins act posttranscriptionally by binding to adenine-and uridinerich elements (AREs) in the 3 untranslated region of a set of target mRNAs, and by increasing mRNA cytoplasmic stability and͞or rate of translation. Here we show that neuronal ELAV-like genes undergo a sustained up-regulation in hippocampal pyramidal cells only of mice and rats that have learned a spatial discrimination paradigm. This learning-specific increase of ELAV-like proteins was localized within cytoplasmic compartments of the somata and proximal dendrites and was associated with the cytoskeleton. This increase was also accompanied by enhanced expression of the GAP-43 gene, known to be regulated mainly posttranscriptionally and whose mRNA is demonstrated here to be an in vivo ELAV-like target. Antisense-mediated knockdown of HuC impaired spatial learning performance in mice and induced a concomitant downregulation of GAP-43 expression. Neuronal ELAV-like proteins could exert learning-induced posttranscriptional control of an array of target genes uniquely suited to subserve substrates of memory storage.

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Section: Resultsmentioning

confidence: 79%

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confidence: 99%

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confidence: 99%

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Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

Quattrone

Pascale

Nogués

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

130

125

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“…also been proposed that the shuttling elav-like proteins are involved in mRNA translation directly (31,32). Similarly, redistribution of HuR protein from the nucleus to the cytoplasm is associated with increased protein production from mRNAs containing AREs with HuR binding sites (33,34). Therefore, HuR may act similarly to HuB and promote polysomal loading of ARE-containing mRNAs.…”

Section: Fig 12mentioning

confidence: 99%

Inhibition of Translation by UAUUUAU and UAUUUUUAU Motifs of the AU-rich RNA Instability Element in the HPV-1 Late 3′ Untranslated Region

Wiklund

Sokolowski²,

Carlsson

et al. 2002

Journal of Biological Chemistry

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The human papillomavirus type 1 (HPV-1) late mRNAs contain a 57-nucleotide adenosine-and uridine-rich RNA instability element termed h1ARE in their late 3 untranslated regions. Here we show that five sequence motifs in the h1ARE (named I-V) affect the mRNA halflife in an additive manner. The minimal inhibitory sequence in motifs I and II was mapped to UAUUUAU, and the minimal inhibitory sequence in motifs III-V was mapped to UAUUUUUAU. We also provide evidence that the same motifs in the AU-RNA instability element inhibit mRNA translation, an effect that was entirely dependent on the presence of a poly(A) tail on the mRNA. Additional experiments demonstrated that the h1ARE interacted directly with the poly(A)-binding protein, suggesting that the h1ARE inhibits translation by interfering with the function of the poly(A)-binding protein.Human papillomaviruses (HPVs) 1 are a group of non-enveloped, double-stranded DNA tumor viruses with tropism for epithelial cells (1, 2). Expression of the late mRNAs is restricted to the terminally differentiated cells in the upper layers of the epithelium and at least four papillomaviruses (bovine papillomavirus type 1 (BPV-1), HPV-1, -16, and -31) have been shown to contain cis-acting inhibitory RNA elements located in the late 3Ј UTR (reviewed in Refs. 3-6). In addition, negative RNA elements have been identified in the HPV-16 L1 and L2 open reading frames (4,7,8).We have previously identified and characterized an inhibitory AU-rich element (ARE) located in the HPV-1 late 3Ј UTR region named h1ARE (4 -6, 9) ( Fig. 1). Using actinomycin D we showed that the presence of the h1ARE reduced the mRNA half-life (10). The minimal inhibitory sequence termed XB spans 57 nucleotides (nt) and contains 93% A and U. The element contains two AUUUA-and the three UUUUU-containing sequences (9, 10). Replacing two uridines (U) with cytidines (C) in each motif inactivated the h1ARE (10). The h1ARE interacts with cellular factors (11,12), which bind to the c-fos ARE (10). Two of the h1ARE binding factors interacted with the wild type h1ARE but not with a functionally inactive mutant of the h1ARE (10). These proteins were identified as HuR and hnRNP C (10, 13), and we later showed that binding of the HuR protein correlates with inhibitory activity of a panel of h1ARE mutants (13). While HuR binds to both AUUUA-and UUUUU-motifs (13), hnRNP C binds exclusively to the UUUUU-motifs (14). The role of hnRNP C in HPV-1 late gene expression is unclear. The HuR protein shuttles between the nucleus and the cytoplasm (15), and we observed that there was an inverse correlation between the levels of HuR in the cell cytoplasm and the inhibitory activity of the h1ARE (16), suggesting that the presence of high levels of HuR in the cytoplasm antagonizes the inhibitory effect of the h1ARE, whereas a primarily nuclear association of HuR is associated with inhibition of HPV-1 late gene expression. Interestingly, the HIV Rev and RRE, and the SRV-1 CTE can overcome the inhibition (9), suggesting that the h1ARE traps th...

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“…HuR is ubiquitously expressed (Ma et al, 1996), while HuB, HuC, and HuD are expressed uniquely in the nervous system. Recent studies indicate that overexpression of neural ELAV-like proteins is sufficient to induce neuronal differentiation in vitro and in vivo (Wakamatsu and Weston, 1997; Akamatsu et al, 1999;Antic et al, 1999;Kasashima et al, 1999). While the exact function and targets of ELAV/Hu proteins remain to be fully elucidated, it seems likely that this family of RNA-binding proteins controls neuronal differentiation by selectively modulating the expression of neural-specific, growth-associated genes.…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding Protein HuD Is Required for GAP-43 mRNA Stability, GAP-43 Gene Expression, and PKC-dependent Neurite Outgrowth in PC12 Cells

Mobarak¹,

Anderson²,

Morin³

et al. 2000

MBoC

126

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The RNA-binding protein HuD binds to a regulatory element in the 3Ј untranslated region (3Ј UTR) of the GAP-43 mRNA. To investigate the functional significance of this interaction, we generated PC12 cell lines in which HuD levels were controlled by transfection with either antisense (pDuH) or sense (pcHuD) constructs. pDuH-transfected cells contained reduced amounts of GAP-43 protein and mRNA, and these levels remained low even after nerve growth factor (NGF) stimulation, a treatment that is normally associated with protein kinase C (PKC)-dependent stabilization of the GAP-43 mRNA and neuronal differentiation. Analysis of GAP-43 mRNA stability demonstrated that the mRNA had a shorter half-life in these cells. In agreement with their deficient GAP-43 expression, pDuH cells failed to grow neurites in the presence of NGF or phorbol esters. These cells, however, exhibited normal neurite outgrowth when exposed to dibutyryl-cAMP, an agent that induces outgrowth independently from GAP-43. We observed opposite effects in pcHuD-transfected cells. The GAP-43 mRNA was stabilized in these cells, leading to an increase in the levels of the GAP-43 mRNA and protein. pcHuD cells were also found to grow short spontaneous neurites, a process that required the presence of GAP-43. In conclusion, our results suggest that HuD plays a critical role in PKC-mediated neurite outgrowth in PC12 cells and that this protein does so primarily by promoting the stabilization of the GAP-43 mRNA. INTRODUCTIONIn addition to transcriptional factors, RNA-binding proteins play a critical role in the developmental control of gene expression. Among these is ELAV (embryonic lethal abnormal vision), an RNA-binding protein identified in Drosophila, where the gene is required for normal development and maintenance of the nervous system (Campos et al., 1985;Robinow et al., 1988). In higher vertebrates and mammals, four members of the ELAV-like family have been identified. These are also referred to as Hu proteins, namely HuR (also known as HuA), HuB (Hel-N1), HuC, and HuD, because these are targets of anti-Hu antibodies present in the sera of patients with paraneoplastic encephalomyelitis (Dalmau et al., 1992). HuR is ubiquitously expressed (Ma et al., 1996), while HuB, HuC, and HuD are expressed uniquely in the nervous system. Recent studies indicate that overexpression of neural ELAV-like proteins is sufficient to induce neuronal differentiation in vitro and in vivo (Wakamatsu and Weston, 1997; Akamatsu et al., 1999;Antic et al., 1999;Kasashima et al., 1999). While the exact function and targets of ELAV/Hu proteins remain to be fully elucidated, it seems likely that this family of RNA-binding proteins controls neuronal differentiation by selectively modulating the expression of neural-specific, growth-associated genes.The growth-associated protein GAP-43 is expressed in neurons primarily during the initial establishment and regeneration of neural connections (Skene, 1989;Benowitz and Routtenberg, 1997 Eggen et al., 1995;Chiaramello et al., 1996;Kinney et ...

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Cytoplasmic localization is required for the mammalian ELAV‐like protein HuD to induce neuronal differentiation

Abstract: Background: ELAV-like neuronal RNA-binding proteins are highly conserved in many neuronecontaining organisms and have been implicated in neuronal development and differentiation.

Cited by 110 publications

References 58 publications

Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

Inhibition of Translation by UAUUUAU and UAUUUUUAU Motifs of the AU-rich RNA Instability Element in the HPV-1 Late 3′ Untranslated Region

The RNA-binding Protein HuD Is Required for GAP-43 mRNA Stability, GAP-43 Gene Expression, and PKC-dependent Neurite Outgrowth in PC12 Cells

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