The Neuron Identity Problem: Form Meets Function
Open accessAbstract
A complete understanding of nervous system function cannot be achieved without the identification of its component cell types. In this Perspective, we explore a series of related issues surrounding cell identity and how revolutionary methods for labeling and probing specific neuronal types have clarified this question. Specifically, we ask the following questions: what is the purpose of such diversity, how is it generated, how is it maintained, and, ultimately, how can one unambiguously identity one cell type from another? We suggest that each cell type can be defined by a unique and conserved molecular ground state that determines its capabilities. We believe that gaining an understanding of these molecular barcodes will advance our ability to explore brain function, enhance our understanding of the biochemical basis of CNS disorders, and aid in the development of novel therapeutic strategies.
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Transcriptomic data from development appear consistent with the idea that early development is dominated by transcription-factor cascades and positive feedback, which later give way to activity-dependent feedback that refines neuronal form and synaptic connections.
“Developmental transcriptomic data seems compatible with the hypothesis that that cascades of transcription factors and positive feedback autoregulatory loops predominate early in development, but pass the baton to activity-dependent feedback mechanisms that fine-tune neuronal morphology and synaptic connectivity (see (Fishell and Heintz, 2013; Kepecs and Fishell, 2014) for review).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Fishell and Heintz, 2013
Cites
A novel multigene family may encode odorant receptors: A molecular basis for odor recognition
Buck, L., & Axel, R. (1991) · Cell · doi:10.1016/0092-8674(91)90418-x · Cited by 4,987 · see citing works
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451 · see citing works
Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129 · see citing works
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., et al. (1995) · Science · doi:10.1126/science.7792600 · Cited by 2,785 · see citing works
The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain
Kriaucionis, S., & Heintz, N. (2009) · Science · doi:10.1126/science.1169786 · Cited by 2,700 · see citing works
Self-citationA gene expression atlas of the central nervous system based on bacterial artificial chromosomes
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., et al. (2003) · Nature · doi:10.1038/nature02033 · Cited by 2,108 · see citing works
Self-citationMeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription
Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., & Zoghbi, H. Y. (2008) · Science · doi:10.1126/science.1153252 · Cited by 1,823 · see citing works
The role of acetylcholine in learning and memory
Hasselmo, M. E. (2006) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2006.09.002 · Cited by 1,693 · see citing works
A translational profiling approach for the molecular characterization of CNS cell types
Heiman, M., Schaefer, A., Gong, S., Peterson, J. D., Day, M., Ramsey, K. E., Suárez-Fariñas, M., Schwarz, C., Stephan, D. A., Surmeier, D. J., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.028 · Cited by 1,134 · see citing works
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Ule, J., Jensen, K. B., Ruggiu, M., Mele, A., Ule, A., & Darnell, R. B. (2003) · Science · doi:10.1126/science.1090095 · Cited by 1,120 · see citing works
Application of a translational profiling approach for the comparative analysis of CNS cell types
Doyle, J. P., Dougherty, J. D., Heiman, M., Schmidt, E. F., Stevens, T. R., Ma, G., Bupp, S., Shrestha, P., Shah, R. D., Doughty, M. L., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.029 · Cited by 912 · see citing works
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Letzkus, J. J., Wolff, S. B. E., Meyer, E. M. M., Tovote, P., Courtin, J., Herry, C., & Lüthi, A. (2011) · Nature · doi:10.1038/nature10674 · Cited by 840 · see citing works
New insights into the classification and nomenclature of cortical GABAergic interneurons
DeFelipe, J., López-Cruz, P. L., Benavides-Piccione, R., Bielza, C., Larrañaga, P., Anderson, S., Burkhalter, A., Cauli, B., Fairén, A., Feldmeyer, D., et al. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3444 · Cited by 833 · see citing works
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Gerfen, C. R., Paletzki, R., & Heintz, N. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.016 · Cited by 647 · see citing works
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West, A. E., & Greenberg, M. E. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005744 · Cited by 532 · see citing works
Molecular taxonomy of major neuronal classes in the adult mouse forebrain
Sugino, K., Hempel, C. M., Miller, M. N., Hattox, A. M., Shapiro, P., Wu, C., Huang, Z. J., & Nelson, S. B. (2006) · Nature Neuroscience · doi:10.1038/nn1618 · Cited by 521 · see citing works
Genomic anatomy of the hippocampus
Thompson, C. L., Pathak, S. D., Jeromin, A., Ng, L. L., MacPherson, C. R., Mortrud, M. T., Cusick, A., Riley, Z. L., Sunkin, S. M., Bernard, A., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.12.008 · Cited by 403 · see citing works
The determination of projection neuron identity in the developing cerebral cortex
Leone, D. P., Srinivasan, K., Chen, B., Alcamo, E., & McConnell, S. K. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.05.006 · Cited by 382 · see citing works
The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain
Gehman, L. T., Stoilov, P., Maguire, J., Damianov, A., Lin, C.-H., Shiue, L., Ares, M., Mody, I., & Black, D. L. (2011) · Nature Genetics · doi:10.1038/ng.841 · Cited by 331 · see citing works
The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes
Butt, S. J. B., Sousa, V. H., Fuccillo, M. V., Hjerling-Leffler, J., Miyoshi, G., Kimura, S., & Fishell, G. (2008) · Neuron · doi:10.1016/j.neuron.2008.07.031 · Cited by 330 · see citing works
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Iijima, T., Wu, K., Witte, H., Hanno-Iijima, Y., Glatter, T., Richard, S., & Scheiffele, P. (2011) · Cell · doi:10.1016/j.cell.2011.11.028 · Cited by 279 · see citing works
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Awatramani, R., Soriano, P., Rodriguez, C., Mai, J. J., & Dymecki, S. M. (2003) · Nature Genetics · doi:10.1038/ng1228 · Cited by 215 · see citing works
Kruglikov, I., & Rudy, B. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.024 · Cited by 209 · see citing works
Shifting the paradigm: new approaches for characterizing and classifying neurons
Bernard, A., Sorensen, S. A., & Lein, E. S. (2009) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2009.09.010 · Cited by 26 · see citing works
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Self-citation
- Authors
- Fishell, G., & Heintz, N.
- Affiliations
- New York University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Fishell, Gord
- Heintz, Nathaniel
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 80
- Issue
- 3
- Pages
- 602-612
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2030457340
- Cited by
- 115
- References
- 25
- Citations by year
- 2026: 2 · 2025: 17 · 2024: 8 · 2023: 3 · 2022: 8 · 2020: 4 · 2019: 11 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 15 · 2014: 17
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (HSSN271200723701C)
- National Institute of Mental Health (5 P50 MH090963 P2, P50MH090963, R01MH071679, R01MH095147)
- National Institute on Drug Abuse (RC2DA028968, P30DA035756)
- National Institute of Neurological Disorders and Stroke (P0NS074972, R01NS081297)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- neuronal cell types, molecular ground state, unique molecular identifiers, neuronal heterogeneity, cell identity, nervous system function, central nervous system disorders, treatment options
- MeSH terms
- Animals, Cell Differentiation, Humans, Nervous System, Neurons
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