miR-375 Inhibits Differentiation of Neurites by Lowering HuD Levels
Open accessAbstract
Neuronal development and plasticity are maintained by tightly regulated gene expression programs. Here, we report that the developmentally regulated microRNA miR-375 affects dendrite formation and maintenance. miR-375 overexpression in mouse hippocampus potently reduced dendrite density. We identified the predominantly neuronal RNA-binding protein HuD as a key effector of miR-375 influence on dendrite maintenance. Heterologous reporter analysis verified that miR-375 repressed HuD expression through a specific, evolutionarily conserved site on the HuD 3' untranslated region. miR-375 overexpression lowered both HuD mRNA stability and translation and recapitulated the effects of HuD silencing, which reduced the levels of target proteins with key functions in neuronal signaling and cytoskeleton organization (N-cadherin, PSD-95, RhoA, NCAM1, and integrin alpha1). Moreover, the increase in neurite outgrowth after brain-derived neurotrophic factor (BDNF) treatment was diminished by miR-375 overexpression; this effect was rescued by reexpression of miR-375-refractory HuD. Our findings indicate that miR-375 modulates neuronal HuD expression and function, in turn affecting dendrite abundance.
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HuD mRNA levels are detectable by day 10 of mouse and rat embryonic brain development, peak at E16, and slowly decline until birth.
“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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Abdelmohsen et al. 2010
Quantitative RT-PCR and Western blot analysis revealed relatively minor, although significant, HuD mRNA and protein levels in several nonneuronal tissues including lung, testes, liver, pituitary gland, pancreatic β cells, and fiber cells of the lens.
“In addition to being expressed in various neuronal subpopulations in the CNS and PNS, quantitative RT-PCR and Western blot analysis revealed relatively minor, although significant, HuD mRNA and protein levels in several nonneuronal tissues including lung, testes, liver, pituitary gland, pancreatic β cells, and fiber cells of the lens (Abdelmohsen et al. 2010; Bitel et al. 2010; Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Abdelmohsen et al. 2010
Knockdown of miR-375 in cultured cells and mouse brain prevents neurite outgrowth through negative control of HuD expression.
“Knockdown of miR-375 in cultured cells and mouse brain revealed that this microRNA prevents neurite outgrowth through negative control of HuD expression.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Abdelmohsen et al. 2010
miR-375 targets the 3′ UTR of HuD and decreases its abundance by reducing both its mRNA stability and translation.
“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).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Abdelmohsen et al. 2010
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References 51 · Cited by 134
- Authors
- Abdelmohsen, K., Hutchison, E. R., Lee, E. K., Kuwano, Y., Kim, M. M., Masuda, K., Srikantan, S., Subaran, S. S., Marasa, B. S., Mattson, M. P., & Gorospe, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Abdelmohsen, Kotb
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-09-01
- Volume
- 30
- Issue
- 17
- Pages
- 4197-4210
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2937556
- OpenAlex
- W1969132788
- Cited by
- 134
- References
- 51
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 12 · 2014: 16 · 2013: 15 · 2012: 12
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (Z01AG000518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- miR-375, HUD, dendrite formation, neurite outgrowth, microRNA regulation, RNA-binding proteins, 3' untranslated region, mRNA stability, translation repression, hippocampus, brain-derived neurotrophic factor, N-cadherin, PSD-95, RhoA, CD56, integrin alpha1, neuronal development
- MeSH terms
- ELAV-Like Protein 4, Animals, Cell Line, Dendrites, Gene Expression Regulation, Hippocampus, Humans, Mice, Inbred C57BL, RNA, Messenger, Neurites, RNA Stability, MicroRNAs, Mice, ELAV Proteins, Neurogenesis
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