All Title Author
Keywords Abstract


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

DOI: 10.1371/journal.pcbi.1001049

Full-Text   Cite this paper   Add to My Lib

Abstract:

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.

References

[1]  Bota M, Dong HW, Swanson LW (2003) From gene networks to brain networks. Nat Neurosci 6: 795–799.
[2]  Just MA, Cherkassky VL, Keller TA, Kana RK, Minshew NJ (2007) Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry. Cereb Cortex 17: 951–961.
[3]  Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, et al. (2002) Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 51: 1008–1011.
[4]  Geschwind DH, Levitt P (2007) Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 17: 103–111.
[5]  Sporns O, Tononi G, Kotter R (2005) The human connectome: A structural description of the human brain. PLoS Comput Biol 1: e42.
[6]  Bohland JW, Wu C, Barbas H, Bokil H, Bota M, et al. (2009) A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale. PLoS Comput Biol 5: e1000334.
[7]  Kotter R (2004) Online retrieval, processing, and visualization of primate connectivity data from the CoCoMac database. Neuroinformatics 2: 127–144.
[8]  White JG, Southgate E, Thomson JN, Brenner S (1986) The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 314: 1–340.
[9]  Hugues B, Olivier T (2007) Modeling self-developing biological neural networks. Neurocomputing 70: 2723–2734.
[10]  Sporns O, Kotter R (2004) Motifs in brain networks. PLoS Biol 2: e369.
[11]  Hilgetag CC, Kaiser M (2004) Clustered organization of cortical connectivity. Neuroinformatics 2: 353–360.
[12]  Scannell JW, Blakemore C, Young MP (1995) Analysis of connectivity in the cat cerebral cortex. J Neurosci 15: 1463–1483.
[13]  Costa Lda F, Kaiser M, Hilgetag CC (2007) Predicting the connectivity of primate cortical networks from topological and spatial node properties. BMC Syst Biol 1: 16.
[14]  Perez-Escudero A, de Polavieja GG (2007) Optimally wired subnetwork determines neuroanatomy of Caenorhabditis elegans. Proc Natl Acad Sci U S A 104: 17180–17185.
[15]  Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, et al. (2002) Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A 99: 4465–4470.
[16]  Zapala MA, Hovatta I, Ellison JA, Wodicka L, Del Rio JA, et al. (2005) Adult mouse brain gene expression patterns bear an embryologic imprint. Proc Natl Acad Sci U S A 102: 10357–10362.
[17]  Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, et al. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445: 168–176.
[18]  Bohland JW, Bokil H, Pathak SD, Lee CK, Ng L, et al. (2009) Clustering of spatial gene expression patterns in the mouse brain and comparison with classical neuroanatomy. Methods 50: 105–112.
[19]  Kiryushko D, Berezin V, Bock E (2004) Regulators of neurite outgrowth: role of cell adhesion molecules. Ann N Y Acad Sci 1014: 140–154.
[20]  Gascon E, Vutskits L, Kiss JZ (2007) Polysialic acid-neural cell adhesion molecule in brain plasticity: from synapses to integration of new neurons. Brain Res Rev 56: 101–118.
[21]  Dong HW, Swanson LW, Chen L, Fanselow MS, Toga AW (2009) Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1. Proc Natl Acad Sci U S A 106: 11794–11799.
[22]  Kaufman A, Dror G, Meilijson I, Ruppin E (2006) Gene expression of Caenorhabditis elegans neurons carries information on their synaptic connectivity. PLoS Comput Biol 2: e167.
[23]  Varadan V, Miller DM 3rd, Anastassiou D (2006) Computational inference of the molecular logic for synaptic connectivity in C. elegans. Bioinformatics 22: e497–506.
[24]  Baruch L, Itzkovitz S, Golan-Mashiach M, Shapiro E, Segal E (2008) Using expression profiles of Caenorhabditis elegans neurons to identify genes that mediate synaptic connectivity. PLoS Comput Biol 4: e1000120.
[25]  Bota M, Dong HW, Swanson LW (2005) Brain architecture management system. Neuroinformatics 3: 15–48.
[26]  Bota M, Swanson LW (2008) BAMS Neuroanatomical Ontology: Design and Implementation. Front Neuroinformatics 2: 2.
[27]  Hoffman PN, Cleveland DW, Griffin JW, Landes PW, Cowan NJ, et al. (1987) Neurofilament gene expression: a major determinant of axonal caliber. Proc Natl Acad Sci U S A 84: 3472–3476.
[28]  Hoffman PN, Griffin JW, Price DL (1984) Control of axonal caliber by neurofilament transport. J Cell Biol 99: 705–714.
[29]  Fuentes-Santamaria V, Stein BE, McHaffie JG (2006) Neurofilament proteins are preferentially expressed in descending output neurons of the cat the superior colliculus: a study using SMI-32. Neuroscience 138: 55–68.
[30]  Legendre P, Fortin MJ (1989) Spatial pattern and ecological analysis. Plant Ecology 80: 107–138.
[31]  Smouse PE, Long JC, Sokal RR (1986) Multiple regression and correlation extensions of the Mantel Test of matrix correspondence. Syst Zool 35: 627–632.
[32]  Runko E, Kaprielian Z (2002) Expression of Vema in the developing mouse spinal cord and optic chiasm. J Comp Neurol 451: 289–299.
[33]  Runko E, Kaprielian Z (2004) Caenorhabditis elegans VEM-1, a novel membrane protein, regulates the guidance of ventral nerve cord-associated axons. J Neurosci 24: 9015–9026.
[34]  Lee CK, Sunkin SM, Kuan C, Thompson CL, Pathak S, et al. (2008) Quantitative methods for genome-scale analysis of in situ hybridization and correlation with microarray data. Genome Biol 9: R23.
[35]  Jones AR, Overly CC, Sunkin SM (2009) The Allen Brain Atlas: 5 years and beyond. Nat Rev Neurosci 10: 821–828.
[36]  Chilton JK (2006) Molecular mechanisms of axon guidance. Dev Biol 292: 13–24.
[37]  Yamaguchi Y (2001) Heparan sulfate proteoglycans in the nervous system: their diverse roles in neurogenesis, axon guidance, and synaptogenesis. Semin Cell Dev Biol 12: 99–106.
[38]  Irie A, Yates EA, Turnbull JE, Holt CE (2002) Specific heparan sulfate structures involved in retinal axon targeting. Development 129: 61–70.
[39]  De Angelis E, Watkins A, Schafer M, Brummendorf T, Kenwrick S (2002) Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. Hum Mol Genet 11: 1–12.
[40]  Tojima T, Akiyama H, Itofusa R, Li Y, Katayama H, et al. (2007) Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone. Nat Neurosci 10: 58–66.
[41]  Yan H, Bergner AJ, Enomoto H, Milbrandt J, Newgreen DF, et al. (2004) Neural cells in the esophagus respond to glial cell line-derived neurotrophic factor and neurturin, and are RET-dependent. Dev Biol 272: 118–133.
[42]  Inuzuka M, Hayakawa M, Ingi T (2005) Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis. J Biol Chem 280: 35776–35783.
[43]  Nagata K, Suzuki H, Niiya-Kato A, Kinoshita S, Taketani S, et al. (2006) Neurensin-1 expression in the mouse retina during postnatal development and in the cultured retinal neurons. Brain Res 1081: 65–71.
[44]  Markham K, Schuurmans C, Weiss S (2007) STAT5A/B activity is required in the developing forebrain and spinal cord. Mol Cell Neurosci 35: 272–282.
[45]  Miura H, Oda K, Endo C, Yamazaki K, Shibasaki H, et al. (1993) Progressive degeneration of motor nerve terminals in GAD mutant mouse with hereditary sensory axonopathy. Neuropathol Appl Neurobiol 19: 41–51.
[46]  Ip NY, McClain J, Barrezueta NX, Aldrich TH, Pan L, et al. (1993) The alpha component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 10: 89–102.
[47]  Miotke JA, MacLennan AJ, Meyer RL (2007) Immunohistochemical localization of CNTFRalpha in adult mouse retina and optic nerve following intraorbital nerve crush: evidence for the axonal loss of a trophic factor receptor after injury. J Comp Neurol 500: 384–400.
[48]  Chedotal A, Del Rio JA, Ruiz M, He Z, Borrell V, et al. (1998) Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development 125: 4313–4323.
[49]  Renthal W, Maze I, Krishnan V, Covington HE 3rd, Xiao G, et al. (2007) Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56: 517–529.
[50]  Gu SM, Orth U, Veske A, Enders H, Klunder K, et al. (1996) Five novel mutations in the L1CAM gene in families with X linked hydrocephalus. J Med Genet 33: 103–106.
[51]  Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045–2047.
[52]  Ragland M, Hutter C, Zabetian C, Edwards K (2009) Association between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1) S18Y variant and Parkinson's Disease: a HuGE review and meta-analysis. Am J Epidemiol 170: 1344–1357.
[53]  International Molecular Genetic Study of Autism Consortium (1998) A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum Mol Genet 7: 571–578.
[54]  Sadakata T, Washida M, Iwayama Y, Shoji S, Sato Y, et al. (2007) Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest 117: 931–943.
[55]  Molloy CA, Keddache M, Martin LJ (2005) Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry 10: 741–746.
[56]  Persico AM, D'Agruma L, Maiorano N, Totaro A, Militerni R, et al. (2001) Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 6: 150–159.
[57]  Kwack K, Lee KL, Kim M, Nam M, Bang HJ, et al. (2008) Positive association between the mesoderm specific transcript gene and autism spectrum disorder in a Korean male population. The FASEB Journal 22: 906.908.
[58]  Bonora E, Lamb JA, Barnby G, Sykes N, Moberly T, et al. (2005) Mutation screening and association analysis of six candidate genes for autism on chromosome 7q. Eur J Hum Genet 13: 198–207.
[59]  Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488.
[60]  Kuemerle B, Gulden F, Cherosky N, Williams E, Herrup K (2007) The mouse Engrailed genes: a window into autism. Behav Brain Res 176: 121–132.
[61]  Basu SN, Kollu R, Banerjee-Basu S (2009) AutDB: a gene reference resource for autism research. Nucleic Acids Res 37: D832–836.
[62]  Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, et al. (2004) Autism and abnormal development of brain connectivity. J Neurosci 24: 9228–9231.
[63]  Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, et al. (2009) Predicting human resting-state functional connectivity from structural connectivity. Proc Natl Acad Sci U S A 106: 2035–2040.
[64]  Murray KD, Choudary PV, Jones EG (2007) Nucleus- and cell-specific gene expression in monkey thalamus. Proc Natl Acad Sci U S A 104: 1989–1994.
[65]  Bota M, Swanson LW (2010) Collating and Curating Neuroanatomical Nomenclatures: Principles and Use of the Brain Architecture Knowledge Management System (BAMS). Front Neuroinformatics 4: 3.
[66]  Swanson LW (1999) Brain Maps: Structure of the Rat Brain. Elsevier. 268 p.
[67]  Dong HW (2007) The Allen Atlas: A Digital Brain Atlas of C57BL/6J Male Mouse. Hoboken, NJ: Wiley.
[68]  Swanson LW (2003) Brain Architecture, Understanding the Basic Plan. New York: Oxford University Press.
[69]  Paxinos G, Franklin KBJ (2008) The Mouse Brain in Stereotaxic Coordinates. San Diego: Academic Press.
[70]  Swanson LW (2004) Brain Maps, Third Edition: Structure of the Rat Brain. Oxford: Academic Press. 215 p.
[71]  Mantel N (1967) The detection of disease clustering and a generalized regression approach. Cancer Res 27: 209–220.
[72]  Lee HK, Braynen W, Keshav K, Pavlidis P (2005) ErmineJ: tool for functional analysis of gene expression data sets. BMC Bioinformatics 6: 269.
[73]  Benjamini Y, Hochberg Y (1995) Controlling the False Discovery Rate: a Practical and Powerful Approach to Multiple Testing. J R Stat Soc Series B Stat Methodol 57: 289–300.
[74]  Pavlidis P, Noble WS (2003) Matrix2png: a utility for visualizing matrix data. Bioinformatics 19: 295–296.

Full-Text

comments powered by Disqus