The RNA-binding protein HuD regulates neuronal cell identity and maturation
Open accessAbstract
Neural Hu proteins (HuB/C/D) are RNA-binding proteins that have been shown to induce neuronal differentiation activity when overexpressed in immature neural progenitor cells or undifferentiated neuronal tumors. Newly generated HuD- deficient mice exhibited a transient impaired-cranial-nerve-development phenotype at an early embryonic stage. Adult HuD -deficient mice exhibited an abnormal hind-limb reflex and poor rotarod performance. Analysis of neurosphere formation revealed that the number and self-renewal capacity of the neural stem/progenitor cells were increased in HuD -deficient mice. HuD -deficient primary neurospheres also generated a smaller number of neurons. Cohort analysis of the cellular proliferative activity by using BrdUrd and iododeoxuridine labeling revealed that the number of differentiating quiescent cells in the embryonic cerebral wall was decreased. Long-term administration of BrdUrd revealed that the number of slowly dividing stem cells in the adult subventricular zone was increased in the HuD -deficient mice. Taken together, the results suggest that HuD is required at multiple points during neuronal development, including negative regulation of proliferative activity and neuronal cell-fate acquisition of neural stem/progenitor cells.
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HuD decreases self-renewal capacity and promotes cell cycle exit and differentiation of neuronal stem/progenitor cells from the cerebral cortex of HuD knockout mice.
“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.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Akamatsu et al. 2005
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)
Experimental — accuracy not yet measuredThe abnormal clasping reflex and poor rotarod performance in adult HuD−/− mice suggest a sensory/motor defect and a role for HuD at the axon terminal.
“suggesting a sensory/motor defect in these animals and a role for HuD at the axon terminal (Akamatsu et al. 2005).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Akamatsu et al. 2005
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)
Experimental — accuracy not yet measuredELAVL4 expression decreases self-renewal of neural progenitor cells and promotes deep-layer glutamatergic neuronal differentiation.
“ELAVL4 expression decreases self-renewal of neural progenitor cells and promotes deep-layer glutamatergic neuronal differentiation (Akamatsu et al., 2005; DeBoer et al., 2014; Popovitchenko et al., 2020).”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Akamatsu et al., 2005
The Results (page not provided) show increased self-renewal and reduced neuronal differentiation in neural stem/progenitor cells from HuD-deficient mice, supporting a role for HuD in limiting self-renewal and promoting neuronal differentiation. The paper does not establish that the neurons are specifically deep-layer or glutamatergic, and it tests HuD loss rather than experimentally increasing its expression. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdult 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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Akamatsu et al. 2005
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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Akamatsu et al. 2005
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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Akamatsu et al. 2005
In adult HuD−/− mice, an abnormal clasping reflex and poor performance on the rotarod test were observed.
“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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Akamatsu et al. 2005
Depletion of nElavl in the brain leads to multiple neurological defects.
“Depletion of nElavl in the brain leads to multiple neurological defects124,125.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [124]
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- Authors
- Akamatsu, W., Fujihara, H., Mitsuhashi, T., Yano, M., Shibata, S., Hayakawa, Y., Okano, H. J., Sakakibara, S.-I., Takano, H., Takano, T., Takahashi, T., Noda, T., & Okano, H.
- Affiliations
- Dokkyo University (JP)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-03-11
- Volume
- 102
- Issue
- 12
- Pages
- 4625-4630
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC555491
- OpenAlex
- W1998938482
- Cited by
- 222
- References
- 30
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 16 · 2020: 16 · 2019: 4 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 10 · 2014: 13 · 2013: 10 · 2012: 16
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Keio University
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- HUD, neuronal differentiation, neural stem/progenitor cells, neural stem cell self-renewal, cranial nerve development, subventricular zone, neurosphere formation, cell proliferation, neuronal cell fate
- MeSH terms
- ELAV-Like Protein 4, Animals, Base Sequence, Brain, Cell Differentiation, Cranial Nerves, DNA, Nerve Tissue Proteins, Nervous System, Neurons, RNA-Binding Proteins, Mice, Knockout, Gene Targeting, Multipotent Stem Cells, Cell Proliferation, Mice, ELAV Proteins
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