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Cited by 120RNA Research and SplicingNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

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

Kasashima, Katsumi, Terashima, Kazuhiro, Yamamoto, Koichi, Sakashita, Eiji, Sakamoto, Hiroshi·1999·Genes to Cells
DOI 10.1046/j.1365-2443.1999.00292.x
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Abstract

Background ELAV-like neuronal RNA-binding proteins are highly conserved in many neurone-containing organisms and have been implicated in neuronal development and differentiation. Results Mammalian neurone-specific ELAV-like Hu proteins (HuB, HuC and HuD) and Drosophila ELAV, but not HuR, were found to induce neurite outgrowth when over-expressed in rat PC12 cells. Functional analysis of HuD deletion mutants demonstrated the importance of two conserved RNA-binding domains (RBDs 1 and 3) and the indispensability of the linker region between RBDs 2 and 3 for the neurite-inducing activity. Further analyses suggested the importance of nucleocytoplasmic shuttling of HuD mediated by a novel nuclear export signal (NES) sequence in the linker region for the neurite-inducing activity. Moreover, two HuD deletion mutants containing the linker region dominantly inhibited the wild-type neurite-inducing activity, although they had no neurite-inducing activity per se, suggesting that saturable intracellular trafficking mediated by the linker region is required for the neurite induction by HuD. Interestingly, the same dominant negative mutants significantly inhibited retinoic acid-induced neuronal differentiation of mouse embryonal carcinoma P19 cells. Conclusions Our results suggest the presence of a novel NES in neurone-specific Hu proteins and the importance of their cytoplasmic localization, through nucleocytoplasmic shuttling, for the initiation of neuronal differentiation.

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  • The HuD linker region contains multiple residues that are post-translationally modified and houses the nuclear export signal (NES) and putative nuclear localization signal (NLS).

    “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).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kasashima et al. 1999

  • 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).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kasashima et al. 1999

  • 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).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kasashima et al. 1999

  • 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).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kasashima et al. 1999

  • 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.

    “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).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kasashima et al. 1999

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Authors
Kasashima, K., Terashima, K., Yamamoto, K., Sakashita, E., & Sakamoto, H.
Affiliations
Kobe University (JP)
Corresponding author
Sakamoto, Hiroshi
ORCID
Yamamoto, Koichi
Venue
Genes to Cells
Publisher
Wiley
Published
1999-11
Volume
4
Issue
11
Pages
667-683
ISSN
  • 1356-9597 (ISSN-L)
  • 1365-2443
DOI
10.1046/j.1365-2443.1999.00292.x
OpenAlex
W2033305072
Cited by
120
References
4
Citations by year
2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 9 · 2015: 4 · 2014: 5 · 2013: 8 · 2012: 5
FWCI
2.07
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 785 d)
Locations
  • Genes to Cells (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
HUD, ELAV-like proteins, cytoplasmic localization, nucleocytoplasmic shuttling, nuclear export signal, neurite outgrowth, neuronal differentiation, RNA-binding domain, linker region, dominant-negative mutant, retinoic acid, P19 cells, PC12 cells
MeSH terms
ELAV-Like Protein 4, Amino Acid Sequence, Animals, Biological Transport, Cell Differentiation, Cell Division, Cell Line, Cell Nucleus, Cytoplasm, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Ribonucleoproteins, Subcellular Fractions, Transcription, Genetic, Tretinoin, Signal Transduction, Neurites, RNA-Binding Proteins, PC12 Cells, Rats, ELAV Proteins

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