Identification of Neuronal Nuclei (NeuN) as Fox-3, a New Member of the Fox-1 Gene Family of Splicing Factors
Open accessAbstract
NeuN (neuronal nuclei) is a neuron-specific nuclear protein which is identified by immunoreactivity with a monoclonal antibody, anti-NeuN. Anti-NeuN has been used widely as a reliable tool to detect most postmitotic neuronal cell types in neuroscience, developmental biology, and stem cell research fields as well as diagnostic histopathology. To date, however, the identity of its antigen, NeuN itself, has been unknown. Here, we identify NeuN as the Fox-3 gene product by providing the following evidence: 1) Mass spectrometry analysis of anti-NeuN immunoreactive protein yields the Fox-3 amino acid sequence. 2) Recombinant Fox-3 is recognized by anti-NeuN. 3) Short hairpin RNAs targeting Fox-3 mRNA down-regulate NeuN expression. 4) Fox-3 expression is restricted to neural tissues. 5) Anti-Fox-3 immunostaining and anti-NeuN immunostaining overlap completely in neuronal nuclei. We also show that a protein cross-reactive with anti-NeuN is the synaptic vesicle protein, synapsin I. Anti-NeuN recognizes synapsin I in immunoblots with one order of magnitude lower affinity than Fox-3, and does not recognize synapsin I using immunohistology. Fox-3 (also called hexaribonucleotide-binding protein 3 and D11Bwg0517e) contains an RNA recognition motif and is classified as a member of the Fox-1 gene family that binds specifically to an RNA element, UGCAUG. We demonstrate that Fox-3 functions as a splicing regulator using neural cell-specific alternative splicing of the non-muscle myosin heavy chain II-B pre-mRNA as a model. Identification of NeuN as Fox-3 clarifies an important element of neurobiology research.
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Previous work has reported covariation of the loss of cortical layer 5 neurons in 5×FAD mice with levels of Aβ42 deposition.
“Previous work has reported covariation of the loss of cortical layer 5 neurons in 5×FAD mice with levels of Aβ42 deposition53.”
From Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice (2026) · cites this paper as [53]
The NeuN/Fox-3 identification section describes neuronal staining, and the cross-reactivity section examines anti-NeuN staining; neither addresses neuron loss in 5×FAD mice. Searches for cortical layer 5 neuron loss, 5×FAD, and Aβ42 deposition found no passage reporting the claimed covariation. Page numbers are unavailable in our copy. (LLM, conf=0.76)
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References 41 · Cited by 398
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- Authors
- Kim, K. K., Adelstein, R. S., & Kawamoto, S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kawamoto, Sachiyo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 284
- Issue
- 45
- Pages
- 31052-31061
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2781505
- OpenAlex
- W2055353932
- Cited by
- 398
- References
- 41
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 21 · 2023: 24 · 2022: 16 · 2021: 21 · 2020: 19 · 2019: 16 · 2018: 26 · 2017: 29 · 2016: 33 · 2015: 31 · 2014: 32 · 2013: 27 · 2012: 17
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- 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
- NeuN, splicing factors, alternative splicing, RNA recognition motif, synapsin I, postmitotic neurons, shRNA knockdown, monoclonal antibody cross-reactivity
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Cells, Cultured, DNA-Binding Proteins, Multigene Family, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Nuclear Proteins, RNA Splicing, Sequence Alignment, RNA-Binding Proteins, Myosin Heavy Chains, Protein Transport, Nonmuscle Myosin Type IIB, Mice
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