Article | Published:

Genome-wide atlas of gene expression in the adult mouse brain

Nature volume 445, pages 168176 (11 January 2007) | Download Citation

Subjects

Abstract

Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl Acad. Sci. USA 102, 10357–10362 (2005)

  2. 2.

    , , & Expression profile of 30,000 genes in rat hippocampus using SAGE. Hippocampus 11, 430–444 (2001)

  3. 3.

    et al. Regional and strain-specific gene expression mapping in the adult mouse brain. Proc. Natl Acad. Sci. USA 97, 11038–11043 (2000)

  4. 4.

    et al. A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells. Proc. Natl Acad. Sci. USA 102, 18485–18490 (2005)

  5. 5.

    et al. Single-cell microarray analysis in hippocampus CA1: demonstration and validation of cellular heterogeneity. J. Neurosci. 23, 3607–3615 (2003)

  6. 6.

    et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nature Neurosci. 9, 99–107 (2006)

  7. 7.

    et al. Interneurons of the neocortical inhibitory system. Nature Rev. Neurosci. 5, 793–807 (2004)

  8. 8.

    , , , & Neuropeptide and calcium-binding protein gene expression profiles predict neuronal anatomical type in the juvenile rat. J. Physiol. (Lond.) 567, 401–413 (2005)

  9. 9.

    & Interneuron diversity series: Molecular and genetic tools to study GABAergic interneuron diversity and function. Trends Neurosci. 27, 90–97 (2004)

  10. 10.

    et al. EMAGE: a spatial database of gene expression patterns during mouse embryo development. Nucleic Acids Res. 34, D637–D641 (2006)

  11. 11.

    et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003)

  12. 12.

    , & GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 32, D552–D556 (2004)

  13. 13.

    et al. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306, 2255–2257 (2004)

  14. 14.

    et al. BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system. PLoS Biol. 4, e86 (2006)

  15. 15.

    & Neurogenomics: at the intersection of neurobiology and genome sciences. Nature Neurosci. 7, 429–433 (2004)

  16. 16.

    et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4, P3 (2003)

  17. 17.

    , & Experience-dependent modification of synaptic plasticity in visual cortex. Nature 381, 526–528 (1996)

  18. 18.

    et al. Characterization of CART neurons in the rat and human hypothalamus. J. Comp. Neurol. 432, 1–19 (2001)

  19. 19.

    et al. Connective tissue growth factor: a novel marker of layer VII neurons in the rat cerebral cortex. Neuroscience 119, 43–52 (2003)

  20. 20.

    , & Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J. Neurosci. 6, 2950–2967 (1986)

  21. 21.

    & Loss of recent memory after bilateral hippocampal lesions. 1957. J. Neuropsychiatry Clin. Neurosci. 12, 103–113 (2000)

  22. 22.

    Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J. Psychol. Neurol. (Lpz.) 46, 113–177 (1934)

  23. 23.

    & The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989)

  24. 24.

    , & Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat. J. Comp. Neurol. 295, 580–623 (1990)

  25. 25.

    , & Early specification and autonomous development of cortical fields in the mouse hippocampus. Development 124, 4959–4970 (1997)

  26. 26.

    , & Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. J. Neurosci. 24, 3879–3889 (2004)

  27. 27.

    , & Synaptic adhesion molecules. Curr. Opin. Cell Biol. 15, 621–632 (2003)

  28. 28.

    The longitudinal axis of the hippocampal formation: its anatomy, circuitry, and role in cognitive function. Rev. Neurosci. 13, 183–194 (2002)

  29. 29.

    & Functional differentiation in the hippocampus. Hippocampus 8, 608–619 (1998)

  30. 30.

    et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci. Biobehav. Rev. 28, 273–283 (2004)

  31. 31.

    , & The Parasagittal Zonation of the Cerebellar Cortex in Cat and Monkey: Topography, Distribution of Acetylcholinesterase, and Development (ed. King, E. S.) (Liss, New York, 1987)

  32. 32.

    & The compartmentalization of the cerebellum. Annu. Rev. Neurosci. 20, 61–90 (1997)

  33. 33.

    & Aldolase C/zebrin II and the regionalization of the cerebellum. J. Mol. Neurosci. 6, 147–158 (1995)

  34. 34.

    & Parasagittal organization of the rat cerebellar cortex: direct comparison of Purkinje cell compartments and the organization of the spinocerebellar projection. J. Comp. Neurol. 291, 79–102 (1990)

  35. 35.

    & Encephalopsin: a novel mammalian extraretinal opsin discretely localized in the brain. J. Neurosci. 19, 3681–3690 (1999)

  36. 36.

    , , & Analysis of subcellularly localized mRNAs using in situ hybridization, mRNA amplification, and expression profiling. Neurochem. Res. 27, 1065–1077 (2002)

  37. 37.

    & A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273, 1402–1406 (1996)

  38. 38.

    , & Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288, 1254–1257 (2000)

  39. 39.

    et al. In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J. Neurosci. 10, 1788–1798 (1990)

  40. 40.

    et al. Spatial segregation of mRNA encoding myelin-specific proteins. Proc. Natl Acad. Sci. USA 84, 7773–7777 (1987)

  41. 41.

    , , & RNA transport and local control of translation. Annu. Rev. Cell Dev. Biol. 21, 223–245 (2005)

  42. 42.

    et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005)

  43. 43.

    et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002)

  44. 44.

    & Prediction of cis-regulatory elements using binding site matrices—the successes, the failures and the reasons for both. Curr. Opin. Genet. Dev. 15, 395–402 (2005)

  45. 45.

    , , & NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005)

  46. 46.

    , & A genetic method for selective and quickly reversible silencing of Mammalian neurons. J. Neurosci. 22, 5287–5290 (2002)

  47. 47.

    et al. A genetic approach to visualization of multisynaptic neural pathways using plant lectin transgene. Neuron 22, 33–41 (1999)

  48. 48.

    et al. Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science 291, 2608–2613 (2001)

  49. 49.

    et al. Novel approaches to monitor and manipulate single neurons in vivo. J. Neurosci. 24, 9223–9227 (2004)

  50. 50.

    et al. Neuroinformatics for genome-wide 3-D gene expression mapping in the mouse brain. IEEE Trans. Comput. Biol. Bioinform. (in the press).

  51. 51.

    & in Handbook of Medical Imaging: Processing and Analysis (ed. Bankman, I. N.) (Academic Press, San Diego, 2000)

  52. 52.

    & Alignment by maximization of mutual information. Int. J. Comput. Vis. 24, 137–154 (1997)

  53. 53.

    & Image Processing and Analysis: Variation, PDE, Wavelet, and Stochastic Methods (Society for Industrial and Applied Mathematics, Philadelphia, 2005)

  54. 54.

    , , & Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J. Comp. Neurol. 485, 1–10 (2005)

  55. 55.

    Brain Maps: Structure of the Rat Brain (Elsevier, Amsterdam, 2004)

Download references

Acknowledgements

This work was sponsored by the Allen Institute for Brain Science. The authors wish to thank the Allen Institute founders, P. G. Allen and J. Patton, for their vision, encouragement and support. We also wish to thank key Institute advisors, K. Dooley and S. Coliton, as well as the Scientific Advisory Board for the Atlas project, M. Tessier-Lavigne, D. Anderson, C. Dulac, R. Gibbs, S. Paul, G. Schuler, A. W. Toga and J. Takahashi, for their scientific guidance and dedication to the successful execution of the Atlas project. We would particularly like to acknowledge D. Anderson for his role in the conceptual genesis and continual refinement of Atlas goals, as well as M. Tessier-Lavigne for key scientific and organizational leadership throughout the project. We also thank C. Jennings for his critical reading of the manuscript.

Author Contributions Neuroscience Group: E.S.L. (group leader), A.B., L.C., M.P.H., M.T.M, C.L.T., T.A.Z. Informatics Group: M.J.H. (group leader), C.L.K., C.L., L.L.N., S.D.P. Production Groups: Allen Institute for Brain Science: P.E.W. (group leader), S.M.S. (group leader), R.A.J. (group leader), M.A., A.F.B., E.J.B., S.D., N.R.D., A.L.D., T.D., E.D., M.J.D., J.G.D., A.J.E., L.K.E., S.R.F., S.N.G., K.J.G., K.R.H., M.R.H., J.M.K., R.H.K., J.H.L., T.A.L., L.T.L., R.J.M., N.F.M., R.N., G.J.O., T.H.P., S.E.P., O.C.P., R.B.P., Z.L.R., H.R.R., S.A.R., J.J.R., N.R.S., K.S., N.V.S., T.S., C.R.S., S.C.S., K.A.S., N.N.S., K.-R.S., L.R.V., R.M.W., C.K.W., V.Y.W., X.F.Y.; Baylor College of Medicine: C.T. (group leader), N.A., L.C. (Li Chen), T.-M.C., A.C., R.F., A.J.L., Y.L., M.J.R., A.T., M.W., M.B.Y., B.Z.; Max Planck Institute: G.E. (group leader), A.V. Technology Group: C.N.D. (group leader), C.D.T. (group leader), A.B. (Amy Bensinger), K.S.B., M.C.C., J.C., B.E.C., T.A.D., B.J.D., T.P.F., C.F. (Cliff Frensley), D.P.J., P.T.K., R.K., A.R.L., K.D.L., J.M., B.I.S., A.J.S., M.S., R.C.Y., B.L.Y. Other: H.-W.D., B.A.F., C.F. and J.J.M., Allen Reference Atlas generation; J.G.H., data annotation; C.C.O., critical review and manuscript preparation; M.S.B., overall project leadership 2003–2004; A.R.J., overall project leadership 2004–present.

Disclaimer The Nature Publishing Group has a business collaboration with the Allen Institute for the creation and maintenance of the Neuroscience gateway (http://www.brainatlas.org), but has no role in generating or curating the Allen Brain Atlas database content. As always, Nature Editors have been fully independent and solely responsible for the editorial content and peer review of this research article.

Author information

Author notes

    • Ed S. Lein
    •  & Michael J. Hawrylycz

    These authors contributed equally to this work.

    • Mark S. Boguski
    •  & Axel Visel

    Present addresses: Division of Genome and Proteome Sciences, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.S.B.); Lawrence Berkeley National Laboratory, Genomics Division, MS84-171, 1 Cyclotron Road, Berkeley, California 94720, USA (A.V.).

Affiliations

  1. Allen Institute for Brain Science, Seattle, Washington 98103, USA

    • Ed S. Lein
    • , Michael J. Hawrylycz
    • , Mikael Ayres
    • , Amy Bensinger
    • , Amy Bernard
    • , Andrew F. Boe
    • , Mark S. Boguski
    • , Kevin S. Brockway
    • , Emi J. Byrnes
    • , Lin Chen
    • , Mei Chi Chin
    • , Jimmy Chong
    • , Brian E. Crook
    • , Chinh N. Dang
    • , Suvro Datta
    • , Nick R. Dee
    • , Aimee L. Desaki
    • , Tsega Desta
    • , Ellen Diep
    • , Tim A. Dolbeare
    • , Matthew J. Donelan
    • , Hong-Wei Dong
    • , Jennifer G. Dougherty
    • , Ben J. Duncan
    • , Amanda J. Ebbert
    • , Lili K. Estin
    • , Casey Faber
    • , Benjamin A. Facer
    • , Shanna R. Fischer
    • , Tim P. Fliss
    • , Cliff Frensley
    • , Sabrina N. Gates
    • , Katie J. Glattfelder
    • , Kevin R. Halverson
    • , Matthew R. Hart
    • , John G. Hohmann
    • , Maureen P. Howell
    • , Darren P. Jeung
    • , Rebecca A. Johnson
    • , Patrick T. Karr
    • , Reena Kawal
    • , Jolene M. Kidney
    • , Rachel H. Knapik
    • , Chihchau L. Kuan
    • , James H. Lake
    • , Annabel R. Laramee
    • , Kirk D. Larsen
    • , Christopher Lau
    • , Tracy A. Lemon
    • , Lon T. Luong
    • , Jesse Michaels
    • , Judith J. Morgan
    • , Rebecca J. Morgan
    • , Marty T. Mortrud
    • , Nerick F. Mosqueda
    • , Lydia L. Ng
    • , Randy Ng
    • , Geralyn J. Orta
    • , Caroline C. Overly
    • , Tu H. Pak
    • , Sheana E. Parry
    • , Sayan D. Pathak
    • , Owen C. Pearson
    • , Ralph B. Puchalski
    • , Zackery L. Riley
    • , Hannah R. Rockett
    • , Stephen A. Rowland
    • , Joshua J. Royall
    • , Nadia R. Sarno
    • , Katherine Schaffnit
    • , Nadiya V. Shapovalova
    • , Taz Sivisay
    • , Clifford R. Slaughterbeck
    • , Simon C. Smith
    • , Kimberly A. Smith
    • , Bryan I. Smith
    • , Andy J. Sodt
    • , Nick N. Stewart
    • , Kenda-Ruth Stumpf
    • , Susan M. Sunkin
    • , Madhavi Sutram
    • , Carey D. Teemer
    • , Carol L. Thompson
    • , Lee R. Varnam
    • , Ray M. Whitlock
    • , Paul E. Wohnoutka
    • , Crissa K. Wolkey
    • , Victoria Y. Wong
    • , Rob C. Young
    • , Brian L. Youngstrom
    • , Xu Feng Yuan
    • , Theresa A. Zwingman
    •  & Allan R. Jones
  2. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Nancy Ao
    • , Li Chen
    • , Tsuey-Ming Chen
    • , Aneta Czaplinska
    • , Rick Fields
    • , Agnes J. Liang
    • , Ying Liu
    • , Marcos J. Ruiz
    • , Angelene Tam
    • , Christina Thaller
    • , Matthew Wood
    • , Murat B. Yaylaoglu
    •  & Bin Zhang
  3. Department of Genes and Behavior, Max Planck Institute of Biophysical Chemistry, 37077 Goettingen, Germany

    • Gregor Eichele
    •  & Axel Visel

Authors

  1. Search for Ed S. Lein in:

  2. Search for Michael J. Hawrylycz in:

  3. Search for Nancy Ao in:

  4. Search for Mikael Ayres in:

  5. Search for Amy Bensinger in:

  6. Search for Amy Bernard in:

  7. Search for Andrew F. Boe in:

  8. Search for Mark S. Boguski in:

  9. Search for Kevin S. Brockway in:

  10. Search for Emi J. Byrnes in:

  11. Search for Lin Chen in:

  12. Search for Li Chen in:

  13. Search for Tsuey-Ming Chen in:

  14. Search for Mei Chi Chin in:

  15. Search for Jimmy Chong in:

  16. Search for Brian E. Crook in:

  17. Search for Aneta Czaplinska in:

  18. Search for Chinh N. Dang in:

  19. Search for Suvro Datta in:

  20. Search for Nick R. Dee in:

  21. Search for Aimee L. Desaki in:

  22. Search for Tsega Desta in:

  23. Search for Ellen Diep in:

  24. Search for Tim A. Dolbeare in:

  25. Search for Matthew J. Donelan in:

  26. Search for Hong-Wei Dong in:

  27. Search for Jennifer G. Dougherty in:

  28. Search for Ben J. Duncan in:

  29. Search for Amanda J. Ebbert in:

  30. Search for Gregor Eichele in:

  31. Search for Lili K. Estin in:

  32. Search for Casey Faber in:

  33. Search for Benjamin A. Facer in:

  34. Search for Rick Fields in:

  35. Search for Shanna R. Fischer in:

  36. Search for Tim P. Fliss in:

  37. Search for Cliff Frensley in:

  38. Search for Sabrina N. Gates in:

  39. Search for Katie J. Glattfelder in:

  40. Search for Kevin R. Halverson in:

  41. Search for Matthew R. Hart in:

  42. Search for John G. Hohmann in:

  43. Search for Maureen P. Howell in:

  44. Search for Darren P. Jeung in:

  45. Search for Rebecca A. Johnson in:

  46. Search for Patrick T. Karr in:

  47. Search for Reena Kawal in:

  48. Search for Jolene M. Kidney in:

  49. Search for Rachel H. Knapik in:

  50. Search for Chihchau L. Kuan in:

  51. Search for James H. Lake in:

  52. Search for Annabel R. Laramee in:

  53. Search for Kirk D. Larsen in:

  54. Search for Christopher Lau in:

  55. Search for Tracy A. Lemon in:

  56. Search for Agnes J. Liang in:

  57. Search for Ying Liu in:

  58. Search for Lon T. Luong in:

  59. Search for Jesse Michaels in:

  60. Search for Judith J. Morgan in:

  61. Search for Rebecca J. Morgan in:

  62. Search for Marty T. Mortrud in:

  63. Search for Nerick F. Mosqueda in:

  64. Search for Lydia L. Ng in:

  65. Search for Randy Ng in:

  66. Search for Geralyn J. Orta in:

  67. Search for Caroline C. Overly in:

  68. Search for Tu H. Pak in:

  69. Search for Sheana E. Parry in:

  70. Search for Sayan D. Pathak in:

  71. Search for Owen C. Pearson in:

  72. Search for Ralph B. Puchalski in:

  73. Search for Zackery L. Riley in:

  74. Search for Hannah R. Rockett in:

  75. Search for Stephen A. Rowland in:

  76. Search for Joshua J. Royall in:

  77. Search for Marcos J. Ruiz in:

  78. Search for Nadia R. Sarno in:

  79. Search for Katherine Schaffnit in:

  80. Search for Nadiya V. Shapovalova in:

  81. Search for Taz Sivisay in:

  82. Search for Clifford R. Slaughterbeck in:

  83. Search for Simon C. Smith in:

  84. Search for Kimberly A. Smith in:

  85. Search for Bryan I. Smith in:

  86. Search for Andy J. Sodt in:

  87. Search for Nick N. Stewart in:

  88. Search for Kenda-Ruth Stumpf in:

  89. Search for Susan M. Sunkin in:

  90. Search for Madhavi Sutram in:

  91. Search for Angelene Tam in:

  92. Search for Carey D. Teemer in:

  93. Search for Christina Thaller in:

  94. Search for Carol L. Thompson in:

  95. Search for Lee R. Varnam in:

  96. Search for Axel Visel in:

  97. Search for Ray M. Whitlock in:

  98. Search for Paul E. Wohnoutka in:

  99. Search for Crissa K. Wolkey in:

  100. Search for Victoria Y. Wong in:

  101. Search for Matthew Wood in:

  102. Search for Murat B. Yaylaoglu in:

  103. Search for Rob C. Young in:

  104. Search for Brian L. Youngstrom in:

  105. Search for Xu Feng Yuan in:

  106. Search for Bin Zhang in:

  107. Search for Theresa A. Zwingman in:

  108. Search for Allan R. Jones in:

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ed S. Lein or Allan R. Jones.

Supplementary information

PDF files

  1. 1.

    Supplemental Methods 1

    Detailed methodologies for tissue processing, probe design and generation, data generation, and image acquisition used for the Allen Brain Atlas project

  2. 2.

    Supplemental Methods 3

    Detailed methodologies used to generate the Allen Reference Atlas

  3. 3.

    Supplemental Data 2

    Side-by-side image comparison of non-isotopic in situ hybridization (ISH) data generated for the Allen Brain Atlas project to comparable radioactive ISH data. Accompanies Supplemental Data 1

  4. 4.

    Supplemental Data 3

    Control data demonstrating the reproducibility of the ABA ISH platform across conditions and across the duration of the ABA project

Word documents

  1. 1.

    Supplemental Methods 2

    Detailed methodologies for informatics-based image quantification and mapping of ISH data to a common 3D coordinate system for genome-wide analysis

  2. 2.

    Supplemental Methods 4

    Description of methods used for voxel-based correlation analysis

  3. 3.

    Supplemental Data 1

    Comparison of non-isotopic in situ hybridization (ISH) data generated for the Allen Brain Atlas project to comparable radioactive ISH data from other sources

  4. 4.

    Supplemental Data 4

    Comparison of expression patterns of the ligand-gated ion channel family to available literature and other data sources, as well as methodology for fine-detailed expert annotation of the ligand-gated ion channel family in the neocortex

Excel files

  1. 1.

    Supplemental Data 5

    Detailed expert annotation of the complete ligand-gated ion channel family in layers of the neocortex. Accompanies Supplemental Data 4

  2. 2.

    Supplementary Table 1

    Genes enriched in major cell populations in the brain (neurons, oligodendrocytes, astrocytes, and choroid plexus cells) identified through correlation-based searches seeded with cell-type specific gene expression patterns. Also included are genes with apparent ubiquity as well as genes that do not have detectable expression in the brain

  3. 3.

    Supplemental Table 2

    Gene Ontology (GO) categories over-represented in genes enriched in major neural cell types and in genes that are either apparently ubiquitous or not expressed. Accompanies Supplemental Table 1

  4. 4.

    Supplemental Table 3

    Genes identified as the most specific for each of 12 different major brain regions

  5. 5.

    Supplemental Table 4

    Genes displaying mRNA targeting to dendrites (neurons) or processes (non-neuronal cells)

Image files

  1. 1.

    Supplemental Figure 1

    Genome-wide analysis of expression level vs. percentage of expressing cells in 12 major brain regions

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature05453

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.