HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects
Abstract
Spinal muscular atrophy is an autosomal-recessive neuromuscular disease caused by disruption of the survival of motor neuron (SMN) gene, which promotes cytoplasmic assembly of the splicing core machinery. It remains unclear how a deficiency in SMN results in a disorder leading to selective degeneration of lower motor neurons. We report here that SMN interacts with RNA-binding protein HuD in neurites of motorneuron-derived MN-1 cells. This interaction is mediated through the Tudor domain of SMN and, importantly, naturally occurring Tudor mutations found in patients with severe spinal muscular atrophy (SMA) completely abrogate the interaction, underscoring its relevance to the disease process. We also characterized a regulatory pathway involving coactivator-associated arginine methyltransferase 1 (CARM1) and HuD. Specifically, we show that CARM1 expression is rapidly downregulated, at the protein level, following induction of differentiation through retinoid and neurotrophic signaling. Using purified proteins, we demonstrate that methylation of HuD by CARM1 reduces its interaction with the p21(cip1/waf1) mRNA, showing that CARM1 can directly influence RNA-binding activity. We further demonstrate that this CARM1-dependent regulatory switch mainly controls the activity of HuD in promoting cell-cycle exit, whereas the interaction between HuD and SMN is required for proper recruitment of HuD and its mRNA targets in neuronal RNA granules. Finally, we were able to rescue SMA-like def…
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CARM1 interacts with and methylates an amino acid in the hinge region of rat HuD (Arg236) and mouse HuD (Arg248).
“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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
Methylation of HuD decreases p21cip1/waf1 mRNA stability and maintains neuronal precursor cells in a proliferative state.
“Moreover, methylation of HuD decreased p21cip1/waf1 mRNA stability and maintained neuronal precursor cells in a proliferative state.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
Reduced CARM1 levels increase GAP-43 mRNA expression but have no effect on other known HuD-targeted mRNAs, including Tau and p27.
“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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
Inhibition of HuD methylation or knockdown of CARM1 results in increased p21cip1/waf1 mRNA levels, cell-cycle withdrawal, and neuronal differentiation.
“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.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
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”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hubers et al. 2010
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References 123 · Cited by 138
- Authors
- Hubers, L., Valderrama-Carvajal, H., Laframboise, J., Timbers, J., Sanchez, G., & Côté, J.
- Affiliations
- University of Ottawa (CA)
- Corresponding author
- Côté, Jocelyn
- ORCID
- Côté, Jocelyn
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-11-18
- Volume
- 20
- Issue
- 3
- Pages
- 553-579
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2153049004
- Cited by
- 138
- References
- 123
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 2 · 2018: 8 · 2017: 16 · 2016: 12 · 2015: 7 · 2014: 13 · 2013: 21 · 2012: 17
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-86746)
- Topics
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- spinal muscular atrophy, survival motor neuron protein, HUD, Tudor domain, CARM1, RNA methylation, cell cycle exit, RNA granules, motor neurons, lower motor neuron degeneration, RNA-binding proteins
- MeSH terms
- ELAV-Like Protein 4, Animals, Base Sequence, Cell Cycle, Cell Line, Fluorescent Antibody Technique, Methylation, Muscular Atrophy, Spinal, Mutation, Nerve Growth Factors, Phenotype, Protein-Arginine N-Methyltransferases, Retinol-Binding Proteins, RNA, Messenger, Immunoblotting, Signal Transduction, Gene Expression, Polymerase Chain Reaction, Neurites, Cell Cycle Proteins, RNA, Small Interfering, Mice, ELAV Proteins, Protein Interaction Domains and Motifs, Survival of Motor Neuron 1 Protein, Gene Knockdown Techniques
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