Relationships between Gene Expression and Brain Wiring in the Adult Rodent Brain

We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain “connectome” from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS.

[1]  H Shibasaki,et al.  Progressive degeneration of motor nerve terminals in GAD mutant mouse with hereditary sensory axonopathy , 1993, Neuropathology and applied neurobiology.

[2]  L. Swanson Brain Architecture: Understanding the Basic Plan , 2002 .

[3]  Teiichi Furuichi,et al.  Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. , 2007, The Journal of clinical investigation.

[4]  M. Fortin,et al.  Spatial pattern and ecological analysis , 1989, Vegetatio.

[5]  Paul Pavlidis,et al.  ErmineJ: Tool for functional analysis of gene expression data sets , 2005, BMC Bioinformatics.

[6]  Hideki Enomoto,et al.  Neural cells in the esophagus respond to glial cell line-derived neurotrophic factor and neurturin, and are RET-dependent. , 2004, Developmental biology.

[7]  N. Mantel The detection of disease clustering and a generalized regression approach. , 1967, Cancer research.

[8]  Samuel Weiss,et al.  STAT5A/B activity is required in the developing forebrain and spinal cord , 2007, Molecular and Cellular Neuroscience.

[9]  C. Goodman,et al.  Semaphorins III and IV repel hippocampal axons via two distinct receptors. , 1998, Development.

[10]  William Stafford Noble,et al.  Matrix2png: a utility for visualizing matrix data , 2003, Bioinform..

[11]  Larry W. Swanson,et al.  Brain Maps: Structure of the Rat Brain , 1992 .

[12]  Karl Herrup,et al.  The mouse Engrailed genes: A window into autism , 2007, Behavioural Brain Research.

[13]  Arthur W. Toga,et al.  Genomic–anatomic evidence for distinct functional domains in hippocampal field CA1 , 2009, Proceedings of the National Academy of Sciences.

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

[15]  Luciano da Fontoura Costa,et al.  Predicting the connectivity of primate cortical networks from topological and spatial node properties , 2007, BMC Systems Biology.

[16]  Madoka Inuzuka,et al.  Serinc, an Activity-regulated Protein Family, Incorporates Serine into Membrane Lipid Synthesis* , 2005, Journal of Biological Chemistry.

[17]  Shigeru Kinoshita,et al.  Neurensin-1 expression in the mouse retina during postnatal development and in cultured retinal neurons , 2006, Brain Research.

[18]  Eran Segal,et al.  Using Expression Profiles of Caenorhabditis elegans Neurons To Identify Genes That Mediate Synaptic Connectivity , 2008, PLoS Comput. Biol..

[19]  Ruth A. Carper,et al.  Autism and Abnormal Development of Brain Connectivity , 2004, The Journal of Neuroscience.

[20]  Larry W. Swanson,et al.  Collating and curating neuroanatomical nomenclatures : principles and use of the Brain Architecture Knowledge Management System ( BAMS ) , 2010 .

[21]  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.

[22]  Larry W Swanson,et al.  From gene networks to brain networks , 2003, Nature Neuroscience.

[23]  B. Stein,et al.  Neurofilament proteins are preferentially expressed in descending output neurons of the cat the superior colliculus: A study using SMI-32 , 2006, Neuroscience.

[24]  Larry W. Swanson,et al.  Brain architecture management system , 2007, Neuroinformatics.

[25]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[26]  A. Pérez-Escudero,et al.  Optimally wired subnetwork determines neuroanatomy of Caenorhabditis elegans , 2007, Proceedings of the National Academy of Sciences.

[27]  Isaac Meilijson,et al.  Gene Expression of Caenorhabditis elegans Neurons Carries Information on Their Synaptic Connectivity , 2006, PLoS Comput. Biol..

[28]  Marcus Kaiser,et al.  Clustered organization of cortical connectivity , 2007, Neuroinformatics.

[29]  M. Just,et al.  Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry. , 2007, Cerebral cortex.

[30]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[31]  Zaven Kaprielian,et al.  Caenorhabditis elegans VEM-1, a Novel Membrane Protein, Regulates the Guidance of Ventral Nerve Cord-Associated Axons , 2004, The Journal of Neuroscience.

[32]  Y. Yamaguchi,et al.  Heparan sulfate proteoglycans in the nervous system: their diverse roles in neurogenesis, axon guidance, and synaptogenesis. , 2001, Seminars in cell & developmental biology.

[33]  J W Griffin,et al.  Neurofilament gene expression: a major determinant of axonal caliber. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

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

[35]  J. Chilton Molecular mechanisms of axon guidance. , 2006, Developmental biology.

[36]  Larry W. Swanson,et al.  BAMS Neuroanatomical Ontology: Design and Implementation , 2008, Frontiers Neuroinformatics.

[37]  R. Sokal,et al.  Multiple regression and correlation extensions of the mantel test of matrix correspondence , 1986 .

[38]  Elisabeth Bock,et al.  Regulators of Neurite Outgrowth: Role of Cell Adhesion Molecules , 2004, Annals of the New York Academy of Sciences.

[39]  Lydia Ng,et al.  Clustering of spatial gene expression patterns in the mouse brain and comparison with classical neuroanatomy. , 2010, Methods.

[40]  Jeremy D. Schmahmann,et al.  A Proposal for a Coordinated Effort for the Determination of Brainwide Neuroanatomical Connectivity in Model Organisms at a Mesoscopic Scale , 2009, PLoS Comput. Biol..

[41]  Atsushi Miyawaki,et al.  Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone , 2007, Nature Neuroscience.

[42]  J. Miotke,et al.  Immunohistochemical localization of CNTFRα in adult mouse retina and optic nerve following intraorbital nerve crush: Evidence for the axonal loss of a trophic factor receptor after injury , 2007, The Journal of comparative neurology.

[43]  Edward G Jones,et al.  Nucleus- and cell-specific gene expression in monkey thalamus , 2007, Proceedings of the National Academy of Sciences.

[44]  David M. Miller,et al.  Computational inference of the molecular logic for synaptic connectivity in C. elegans , 2006, ISMB.

[45]  Min Nam,et al.  Positive association between the mesoderm specific transcript gene and autism spectrum disorder in a Korean male population , 2008 .

[46]  Carolyn Hutter,et al.  Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis , 2009, American journal of epidemiology.

[47]  D. Geschwind,et al.  Autism spectrum disorders: developmental disconnection syndromes , 2007, Current Opinion in Neurobiology.

[48]  J. Kiss,et al.  Polysialic acid–neural cell adhesion molecule in brain plasticity: From synapses to integration of new neurons , 2007, Brain Research Reviews.

[49]  S. Kenwrick,et al.  Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. , 2002, Human molecular genetics.

[50]  T. Wassink,et al.  Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder , 2001, Molecular Psychiatry.

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

[52]  Karl J. Friston,et al.  Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations , 2002, Biological Psychiatry.

[53]  Allan R. Jones,et al.  The Allen Brain Atlas: 5 years and beyond , 2009, Nature Reviews Neuroscience.

[54]  D. Pinto,et al.  Structural variation of chromosomes in autism spectrum disorder. , 2008, American journal of human genetics.

[55]  C. Francks,et al.  A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. , 1998, Human molecular genetics.

[56]  Rolf Kötter,et al.  Online retrieval, processing, and visualization of primate connectivity data from the CoCoMac Database , 2007, Neuroinformatics.

[57]  A. Orth,et al.  Large-scale analysis of the human and mouse transcriptomes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Sharmila Banerjee-Basu,et al.  AutDB: a gene reference resource for autism research , 2008, Nucleic Acids Res..

[59]  Rodney Cotterill,et al.  Mutation screening and association analysis of six candidate genes for autism on chromosome 7q , 2005, European Journal of Human Genetics.

[60]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[61]  Atsushi Irie,et al.  Specific heparan sulfate structures involved in retinal axon targeting. , 2002, Development.

[62]  Zaven Kaprielian,et al.  Expression of Vema in the developing mouse spinal cord and optic chiasm , 2002, The Journal of comparative neurology.

[63]  Nancy Y. Ip,et al.  The α component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development , 1993, Neuron.

[64]  O Sporns,et al.  Predicting human resting-state functional connectivity from structural connectivity , 2009, Proceedings of the National Academy of Sciences.

[65]  Olivier Temam,et al.  Modeling self-developing biological neural networks , 2007, Neurocomputing.

[66]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[67]  Guanghua Xiao,et al.  Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli , 2007, Neuron.

[68]  C. Blakemore,et al.  Analysis of connectivity in the cat cerebral cortex , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[69]  Olaf Sporns,et al.  The Human Connectome: A Structural Description of the Human Brain , 2005, PLoS Comput. Biol..

[70]  M. Keddache,et al.  Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression , 2005, Molecular Psychiatry.

[71]  U Orth,et al.  Five novel mutations in the L1CAM gene in families with X linked hydrocephalus. , 1996, Journal of medical genetics.

[72]  O. Sporns,et al.  Motifs in Brain Networks , 2004, PLoS biology.

[73]  J W Griffin,et al.  Control of axonal caliber by neurofilament transport , 1984, The Journal of cell biology.