Quantitative Expression Profile of Distinct Functional Regions in the Adult Mouse Brain

The adult mammalian brain is composed of distinct regions with specialized roles including regulation of circadian clocks, feeding, sleep/awake, and seasonal rhythms. To find quantitative differences of expression among such various brain regions, we conducted the BrainStars (B*) project, in which we profiled the genome-wide expression of ∼50 small brain regions, including sensory centers, and centers for motion, time, memory, fear, and feeding. To avoid confounds from temporal differences in gene expression, we sampled each region every 4 hours for 24 hours, and pooled the samples for DNA-microarray assays. Therefore, we focused on spatial differences in gene expression. We used informatics to identify candidate genes with expression changes showing high or low expression in specific regions. We also identified candidate genes with stable expression across brain regions that can be used as new internal control genes, and ligand-receptor interactions of neurohormones and neurotransmitters. Through these analyses, we found 8,159 multi-state genes, 2,212 regional marker gene candidates for 44 small brain regions, 915 internal control gene candidates, and 23,864 inferred ligand-receptor interactions. We also found that these sets include well-known genes as well as novel candidate genes that might be related to specific functions in brain regions. We used our findings to develop an integrated database (http://brainstars.org/) for exploring genome-wide expression in the adult mouse brain, and have made this database openly accessible. These new resources will help accelerate the functional analysis of the mammalian brain and the elucidation of its regulatory network systems.

[1]  K. Brodmann Vergleichende Lokalisationslehre der Großhirnrinde : in ihren Prinzipien dargestellt auf Grund des Zellenbaues , 1985 .

[2]  J. Lisman,et al.  The molecular basis of CaMKII function in synaptic and behavioural memory , 2002, Nature Reviews Neuroscience.

[3]  J. Uhm,et al.  The transcriptional network for mesenchymal transformation of brain tumours , 2010 .

[4]  S. P. Fodor,et al.  High density synthetic oligonucleotide arrays , 1999, Nature Genetics.

[5]  Elspeth A Bruford,et al.  Classification and nomenclature of all human homeobox genes , 2007, BMC Biology.

[6]  W. Talbot,et al.  A G Protein–Coupled Receptor Is Essential for Schwann Cells to Initiate Myelination , 2009, Science.

[7]  Lily Yan,et al.  Light-Induced Resetting of a Mammalian Circadian Clock Is Associated with Rapid Induction of the mPer1 Transcript , 1997, Cell.

[8]  Zhaohua Lu,et al.  The Duffy antigen receptor for chemokines: structural analysis and expression in the brain , 1996, Journal of leukocyte biology.

[9]  H. Ueda,et al.  Genome-wide Transcriptional Orchestration of Circadian Rhythms inDrosophila * 210 , 2002, The Journal of Biological Chemistry.

[10]  Anthony J. Harmar,et al.  Synchronization and Maintenance of Timekeeping in Suprachiasmatic Circadian Clock Cells by Neuropeptidergic Signaling , 2006, Current Biology.

[11]  K. Kodama,et al.  Anxiolytic Effect of Hepatocyte Growth Factor Infused into Rat Brain , 2005, Neuropsychobiology.

[12]  G. Paxinos The Rat nervous system , 1985 .

[13]  P. Hof,et al.  A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy , 2005, Neuroscience.

[14]  Michael Gormley,et al.  Expression profiles of switch-like genes accurately classify tissue and infectious disease phenotypes in model-based classification , 2008, BMC Bioinformatics.

[15]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[16]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[17]  Johan Auwerx,et al.  Systematic Gene Expression Mapping Clusters Nuclear Receptors According to Their Function in the Brain , 2007, Cell.

[18]  R. Evans,et al.  Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network , 2006, Cell.

[19]  R. James,et al.  Homeobox gene expression in the intestinal epithelium of adult mice. , 1991, The Journal of biological chemistry.

[20]  T. Curran,et al.  BGEM: An In Situ Hybridization Database of Gene Expression in the Embryonic and Adult Mouse Nervous System , 2006, PLoS biology.

[21]  V. Reghunandanan,et al.  Neurotransmitters of the suprachiasmatic nuclei , 2006, Journal of circadian rhythms.

[22]  E. McCabe,et al.  Molecular mechanisms of DAX1 action. , 2004, Molecular genetics and metabolism.

[23]  M. Paradiso,et al.  Neuroscience: Exploring the Brain , 1996 .

[24]  A. Akaike,et al.  Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia? , 1998, FEBS letters.

[25]  Vladislav A Petyuk,et al.  A genome-scale map of expression for a mouse brain section obtained using voxelation. , 2007, Physiological genomics.

[26]  Crispin J. Miller,et al.  Exon level integration of proteomics and microarray data , 2008, BMC Bioinformatics.

[27]  A. Su,et al.  Expression analysis of G Protein-Coupled Receptors in mouse macrophages , 2008, Immunome research.

[28]  Mary Johnson,et al.  Autoradiographic comparison of cholinergic and other transmitter receptors in the normal human hippocampus , 1993, Hippocampus.

[29]  Masahiko Watanabe,et al.  Cbln1 is essential for synaptic integrity and plasticity in the cerebellum , 2005, Nature Neuroscience.

[30]  F. Wright,et al.  Large-Scale Gene Expression Differences Across Brain Regions and Inbred Strains Correlate With a Behavioral Phenotype , 2006, Genetics.

[31]  H. Ono,et al.  Involvement of thyrotropin in photoperiodic signal transduction in mice , 2008, Proceedings of the National Academy of Sciences.

[32]  S. Pradervand,et al.  Homer1a is a core brain molecular correlate of sleep loss , 2007, Proceedings of the National Academy of Sciences.

[33]  Lydia Ng,et al.  Exploration and visualization of gene expression with neuroanatomy in the adult mouse brain , 2008, BMC Bioinformatics.

[34]  Erik D Herzog,et al.  Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons , 2005, Nature Neuroscience.

[35]  Hidetoshi Shimodaira,et al.  Pvclust: an R package for assessing the uncertainty in hierarchical clustering , 2006, Bioinform..

[36]  Pablo A. Iglesias,et al.  MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast , 2007, Nature.

[37]  Yang Liu,et al.  Mouse Brain Organization Revealed Through Direct Genome-Scale TF Expression Analysis , 2004, Science.

[38]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Nasser M. Nasrabadi,et al.  Pattern Recognition and Machine Learning , 2006, Technometrics.

[40]  Jennifer J. Loros,et al.  Chronobiology: Biological Timekeeping , 2009 .

[41]  K. Amunts,et al.  Towards multimodal atlases of the human brain , 2006, Nature Reviews Neuroscience.

[42]  S. Gilbert Principles of Development: Genes and Development , 2000 .

[43]  H. Ueda,et al.  Thyrotrophin in the pars tuberalis triggers photoperiodic response , 2008, Nature.

[44]  D. Ballantyne,et al.  Neurotransmitters and neuromodulators : handbook of receptors and biological effects , 2002 .

[45]  E. Maywood,et al.  The VPAC2 Receptor Is Essential for Circadian Function in the Mouse Suprachiasmatic Nuclei , 2002, Cell.

[46]  Matthew A. Zapala,et al.  Adult mouse brain gene expression patterns bear an embryologic imprint. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  H. Schaller,et al.  Cloning and characterization of a novel G-protein-coupled receptor with homology to galanin receptors , 2004, Neuropharmacology.

[48]  Shawn Mikula,et al.  Internet-enabled high-resolution brain mapping and virtual microscopy , 2007, NeuroImage.

[49]  G. Michalopoulos,et al.  Expression of HGF and cMet in the developing and adult brain. , 1997, Brain research. Developmental brain research.

[50]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[51]  Michael Hawrylycz,et al.  Quantitative methods for genome-scale analysis of in situ hybridization and correlation with microarray data , 2008, Genome Biology.

[52]  T Hori,et al.  Molecular Cloning of a Novel Brain‐Type Na+‐Dependent Inorganic Phosphate Cotransporter , 2000, Journal of neurochemistry.

[53]  Eric E. Schadt,et al.  Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice , 2005, Nature.

[54]  Shane T. Jensen,et al.  Macromolecule biosynthesis: a key function of sleep. , 2007, Physiological genomics.

[55]  B. Schimmer,et al.  Steroidogenic factor 1: a key determinant of endocrine development and function. , 1997, Endocrine reviews.

[56]  C. Saper,et al.  Differential expression of somatostatin receptor subtypes in brain , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[57]  J. Pounds,et al.  Data merging for integrated microarray and proteomic analysis. , 2006, Briefings in functional genomics & proteomics.

[58]  E. Olson,et al.  Restricted expression of homeobox genes distinguishes fetal from adult human smooth muscle cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[59]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

[60]  Hong Wang,et al.  Cholecystokinin-2 (CCK2) receptor-mediated anxiety-like behaviors in rats , 2005, Neuroscience & Biobehavioral Reviews.

[61]  Paul Smith,et al.  EMAGE—Edinburgh Mouse Atlas of Gene Expression: 2008 update , 2007, Nucleic Acids Res..

[62]  Gregor Eichele,et al.  GenePaint.org: an atlas of gene expression patterns in the mouse embryo , 2004, Nucleic Acids Res..

[63]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[64]  Joseph E LeDoux Emotion Circuits in the Brain , 2000 .

[65]  Adam Ertel,et al.  Switch-like genes populate cell communication pathways and are enriched for extracellular proteins , 2008, BMC Genomics.

[66]  Sumio Sugano,et al.  A transcription factor response element for gene expression during circadian night , 2002, Nature.