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Molecular approaches to brain asymmetry and handedness

Key Points

  • The left and right hemispheres of the human brain have distinct functions: for example, the left is normally dominant for language and logical processing, whereas the right is specified for spatial recognition. The segregation of human brain functions between the left and right hemispheres is associated with asymmetries of anatomical structures, such as the Sylvian fissures and the planum temporale.

  • More than 90% of the human population is more skilled with the right hand, which is controlled by the left hemisphere. Language ability is also dominant in the left hemisphere in more than 95% of the right-handed population, whereas it is observed in only 70% of the left-handed population.

  • There seems to be a genetic correlation of language ability and handedness, which are both controlled by the left hemisphere in most humans. Preferred hand use has been observed even at embryonic and fetal stages in humans, long before language ability is developed. Whether hemispheric asymmetry for handedness or language ability appeared first in human evolution still remains a puzzle.

  • Biased handedness is also observed in non-human primates and other mammals. But there does not seem to be a strong preference for either the left or right hand at the population level. How has preferred handedness in humans evolved? Applying genomic approaches, particularly the complete sequencing of the human and chimpanzee genomes, will allow us to gain insight into the evolutionary mechanisms of lateralized human behaviours.

  • Previous studies have revealed that fibroblast growth factor 8 (FGF8), sonic hedgehog (SHH), NODAL, and ion flux and directed cilia movement in embryos have important roles in regulating visceral organ asymmetry. Conserved molecules that regulate body asymmetry are also essential for the regulation of the asymmetry of zebrafish brains. However, patients with a complete reversal of normal organ position, and patients with impaired cilia motility, have normal left-hemisphere dominance for language and handedness. Using a serial analysis of gene expression (SAGE) technique, we measured gene expression levels in the left and right hemispheres in human fetal brains but did not detect differential expression of SHH and NODAL signalling molecules. Molecules and mechanisms that regulate body asymmetry might be distinct from those that regulate brain asymmetry and handedness.

  • Morphogens secreted from the ventral and/or dorsal midlines of the forebrain, or secreted from the anterior cortical region, might be distributed differently between the left and right hemispheres. The different expression levels of morphogens induce differential expression of downstream transcription factors and eventually lead to brain asymmetry.

  • Applying evolutionary and molecular approaches might help us to reveal the mechanisms that regulate brain asymmetry and handedness.

Abstract

In the human brain, distinct functions tend to be localized in the left or right hemispheres, with language ability usually localized predominantly in the left and spatial recognition in the right. Furthermore, humans are perhaps the only mammals who have preferential handedness, with more than 90% of the population more skilful at using the right hand, which is controlled by the left hemisphere. How is a distinct function consistently localized in one side of the human brain? Because of the convergence of molecular and neurological analysis, we are beginning to consider the puzzle of brain asymmetry and handedness at a molecular level.

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Figure 1: Anatomical asymmetries in the human cerebral cortex.
Figure 2: Asymmetrically expressed genes in 12-week-old human fetal brains, detected by serial analysis of gene expression and real-time reverse transcription (RT)-PCR.
Figure 3: Three models of molecular induction of brain asymmetry.
Figure 4: Unilateral polymicrogyria detected using MRI.

References

  1. Levitt, P., Barbe, M. F. & Eagleson, K. L. Patterning and specification of the cerebral cortex. Annu. Rev. Neurosci. 20, 1–24 (1997).

    CAS  PubMed  Google Scholar 

  2. O'Leary, D. D. & Nakagawa, Y. Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr. Opin. Neurobiol. 12, 14–25 (2002).

    CAS  PubMed  Google Scholar 

  3. Grove, E. A. & Fukuchi-Shimogori, T. Generating the cerebral cortical area map. Annu. Rev. Neurosci. 26, 355–380 (2003).

    CAS  PubMed  Google Scholar 

  4. Sur, M. & Rubenstein, J. L. Patterning and plasticity of the cerebral cortex. Science 310, 805–810 (2005).

    CAS  PubMed  Google Scholar 

  5. Rakic, P. Neuronal migration and contact guidance in primate telencephalon. Postgrad. Med. J. 54, 25–40 (1978).

    PubMed  Google Scholar 

  6. O'Leary, D. D. Do cortical areas emerge from a protocortex? Trends Neurosci. 12, 400–406 (1989).

    CAS  PubMed  Google Scholar 

  7. Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988).

    CAS  PubMed  Google Scholar 

  8. Geschwind, D. H. & Miller, B. L. Molecular approaches to cerebral laterality: development and neurodegeneration. Am. J. Med. Genet. 101, 370–381 (2001). Examines expression patterns of genes that regulate body asymmetries in human fetal brains and discusses molecular regulation of brain asymmetry.

    CAS  PubMed  Google Scholar 

  9. Riss, W. Testing a theory of brain function by computer methods. III. Detecting cerebral asymmetry in normal adults. Brain Behav. Evol. 24, 13–20 (1984).

    CAS  PubMed  Google Scholar 

  10. Toga, A. W. & Thompson, P. M. Mapping brain asymmetry. Nature Rev. Neurosci. 4, 37–48 (2003). Overview of brain anatomical asymmetries mapped using modern imaging techniques.

    CAS  Google Scholar 

  11. Van Essen, D. C. A population-average, landmark- and surface-based (PALS) atlas of human cerebral cortex. Neuroimage 28, 635–662 (2005). Maps brain asymmetries and beautifully demonstrates consistent asymmetries in the Sylvian fissures and the superior temporal sulcus.

    PubMed  Google Scholar 

  12. Corballis, M. C. From mouth to hand: gesture, speech, and the evolution of right-handedness. Behav. Brain. Sci. 26, 199–208; discussion 208–260 (2003).

    Google Scholar 

  13. Broca, P. Remarques sur le siège de la faculté du langage articulé, suivies d'une observation d'aphémie (perte de la parole). Bull. Soc. Anthropol. 6, 330–357 (1861) (in French).

    Google Scholar 

  14. Wernicke, C. Der Aphasische Symptomenkomplex: Eine Psychologische Studie auf Anatomischer Basis (Cohn und Welgert, Breslau, 1874) (in German).

    Google Scholar 

  15. Gazzaniga, M. S. Forty-five years of split-brain research and still going strong. Nature Rev. Neurosci. 6, 653–659 (2005).

    CAS  Google Scholar 

  16. Gazzaniga, M. S. Brain and conscious experience. Adv. Neurol. 77, 181–192; discussion 192–193 (1998).

    CAS  PubMed  Google Scholar 

  17. Borod, J. C., Bloom, R. L., Brickman, A. M., Nakhutina, L. & Curko, E. A. Emotional processing deficits in individuals with unilateral brain damage. Appl. Neuropsychol. 9, 23–36 (2002).

    PubMed  Google Scholar 

  18. Rubens, A. B., Mahowald, M. W. & Hutton, J. T. Asymmetry of the lateral (Sylvian) fissures in man. Neurology 26, 620–624 (1976).

    CAS  PubMed  Google Scholar 

  19. Shapleske, J., Rossell, S. L., Woodruff, P. W. & David, A. S. The planum temporale: a systematic, quantitative review of its structural, functional and clinical significance. Brain Res. Brain Res. Rev. 29, 26–49 (1999).

    CAS  PubMed  Google Scholar 

  20. Hirayasu, Y. et al. Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients. Arch. Gen. Psychiatry 57, 692–699 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Geschwind, N. & Levitsky, W. Human brain: left–right asymmetries in temporal speech region. Science 161, 186–187 (1968).

    CAS  PubMed  Google Scholar 

  22. Chi, J. G., Dooling, E. C. & Gilles, F. H. Left–right asymmetries of the temporal speech areas of the human fetus. Arch. Neurol. 34, 346–348 (1977).

    CAS  PubMed  Google Scholar 

  23. Hutsler, J. J. The specialized structure of human language cortex: pyramidal cell size asymmetries within auditory and language-associated regions of the temporal lobes. Brain Lang. 86, 226–242 (2003).

    PubMed  Google Scholar 

  24. Rosen, G. D. Cellular, morphometric, ontogenetic and connectional substrates of anatomical asymmetry. Neurosci. Biobehav. Rev. 20, 607–615 (1996).

    CAS  PubMed  Google Scholar 

  25. Galaburda, A. M., Rosen, G. D. & Sherman, G. F. Individual variability in cortical organization: its relationship to brain laterality and implications to function. Neuropsychologia 28, 529–546 (1990).

    CAS  PubMed  Google Scholar 

  26. Soros, P. et al. Cortical asymmetries of the human somatosensory hand representation in right- and left-handers. Neurosci. Lett. 271, 89–92 (1999).

    CAS  PubMed  Google Scholar 

  27. Amunts, K. et al. Asymmetry in the human motor cortex and handedness. Neuroimage 4, 216–222 (1996).

    CAS  PubMed  Google Scholar 

  28. Volkmann, J., Schnitzler, A., Witte, O. W. & Freund, H. Handedness and asymmetry of hand representation in human motor cortex. J. Neurophysiol. 79, 2149–2154 (1998).

    CAS  PubMed  Google Scholar 

  29. Good, C. D. et al. Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. Neuroimage 14, 685–700 (2001).

    CAS  Google Scholar 

  30. Coren, S. & Porac, C. Fifty centuries of right-handedness: the historical record. Science 198, 631–632 (1977).

    CAS  PubMed  Google Scholar 

  31. Corballis, M. C. The genetics and evolution of handedness. Psychol. Rev. 104, 714–727 (1997).

    CAS  PubMed  Google Scholar 

  32. Klar, A. J. Genetic models for handedness, brain lateralization, schizophrenia, and manic-depression. Schizophr. Res. 39, 207–218 (1999).

    CAS  Google Scholar 

  33. Annett, M. The distribution of manual asymmetry. Br. J. Psychol. 63, 343–358 (1972). Proposes a genetic model for the regulation of cortical asymmetry and handedness.

    CAS  PubMed  Google Scholar 

  34. McManus, I. C. Handedness, language dominance and aphasia: a genetic model. Psychol. Med. Monogr. Suppl. 8, 1–40 (1985). Proposes and discusses a genetic model that leads to preferential handedness in humans.

    CAS  PubMed  Google Scholar 

  35. O'Rahilly, R. & Müller, F. Developmental Stages in Human Embryos (Carnegie Institute of Washington, Publication 637, Washington DC, 1987).

    Google Scholar 

  36. Hepper, P. G., Shahidullah, S. & White, R. Handedness in the human fetus. Neuropsychologia 29, 1107–1111 (1991).

    CAS  PubMed  Google Scholar 

  37. Hepper, P. G., Wells, D. L. & Lynch, C. Prenatal thumb sucking is related to postnatal handedness. Neuropsychologia 43, 313–315 (2005).

    PubMed  Google Scholar 

  38. Chi, J. G., Dooling, E. C. & Gilles, F. H. Gyral development of the human brain. Ann. Neurol. 1, 86–93 (1977).

    CAS  PubMed  Google Scholar 

  39. Galaburda, A. M., LeMay, M., Kemper, T. L. & Geschwind, N. Right–left asymmetrics in the brain. Science 199, 852–856 (1978).

    CAS  PubMed  Google Scholar 

  40. Chiron, C. et al. The right brain hemisphere is dominant in human infants. Brain 120, 1057–1065 (1997).

    PubMed  Google Scholar 

  41. Trevarthen, C. Lateral asymmetries in infancy: implications for the development of the hemispheres. Neurosci. Biobehav. Rev. 20, 571–586 (1996).

    CAS  PubMed  Google Scholar 

  42. Gannon, P. J., Holloway, R. L., Broadfield, D. C. & Braun, A. R. Asymmetry of chimpanzee planum temporale: humanlike pattern of Wernicke's brain language area homolog. Science 279, 220–222 (1998).

    CAS  PubMed  Google Scholar 

  43. Cantalupo, C. & Hopkins, W. D. Asymmetric Broca's area in great apes. Nature 414, 505 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hopkins, W. D., Marino, L., Rilling, J. K. & MacGregor, L. A. Planum temporale asymmetries in great apes as revealed by magnetic resonance imaging (MRI). Neuroreport 9, 2913–2918 (1998).

    CAS  PubMed  Google Scholar 

  45. Hutsler, J. & Galuske, R. A. Hemispheric asymmetries in cerebral cortical networks. Trends Neurosci. 26, 429–435 (2003).

    CAS  PubMed  Google Scholar 

  46. Sherwood, C. C., Broadfield, D. C., Holloway, R. L., Gannon, P. J. & Hof, P. R. Variability of Broca's area homologue in African great apes: implications for language evolution. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 271, 276–285 (2003).

    PubMed  Google Scholar 

  47. Sun, T., Collura, R. V., Ruvolo, M. & Walsh, C. A. Genomic and evolutionary analyses of asymmetrically expressed genes in human fetal left and right cerebral cortex. Cereb. Cortex 16, i18–i25 (2006).

    PubMed  Google Scholar 

  48. Hopkins, W. D. & Cantalupo, C. Individual and setting differences in the hand preferences of chimpanzees (Pan troglodytes): a critical analysis and some alternative explanations. Laterality 10, 65–80 (2005).

    PubMed  PubMed Central  Google Scholar 

  49. McGrew, W. C., Marchant, L. F., Wrangham, R. W. & Klein, H. Manual laterality in anvil use: wild chimpanzees cracking Strychnos fruits. Laterality 4, 79–87 (1999).

    CAS  PubMed  Google Scholar 

  50. Lonsdorf, E. V. & Hopkins, W. D. Wild chimpanzees show population-level handedness for tool use. Proc. Natl Acad. Sci. USA 102, 12634–12638 (2005). Shows that preferential hand use in wild chimpanzees depends on the specific task.

    CAS  PubMed  Google Scholar 

  51. Wells, D. L. Lateralised behaviour in the domestic dog, Canis familiaris. Behav. Processes 61, 27–35 (2003).

    PubMed  Google Scholar 

  52. Tan, U. Paw preferences in dogs. Int. J. Neurosci. 32, 825–829 (1987).

    CAS  PubMed  Google Scholar 

  53. Fabre-Thorpe, M., Fagot, J., Lorincz, E., Levesque, F. & Vauclair, J. Laterality in cats: paw preference and performance in a visuomotor activity. Cortex 29, 15–24 (1993).

    CAS  PubMed  Google Scholar 

  54. Bulman-Fleming, M. B., Bryden, M. P. & Rogers, T. T. Mouse paw preference: effects of variations in testing protocol. Behav. Brain Res. 86, 79–87 (1997).

    CAS  PubMed  Google Scholar 

  55. Waters, N. S. & Denenberg, V. H. Analysis of two measures of paw preference in a large population of inbred mice. Behav. Brain Res. 63, 195–204 (1994).

    CAS  PubMed  Google Scholar 

  56. Guven, M., Elalmis, D. D., Binokay, S. & Tan, U. Population-level right-paw preference in rats assessed by a new computerized food-reaching test. Int. J. Neurosci. 113, 1675–1689 (2003).

    PubMed  Google Scholar 

  57. Signore, P. et al. An assessment of handedness in mice. Physiol. Behav. 49, 701–704 (1991).

    CAS  PubMed  Google Scholar 

  58. Biddle, F. G., Coffaro, C. M., Ziehr, J. E. & Eales, B. A. Genetic variation in paw preference (handedness) in the mouse. Genome 36, 935–943 (1993).

    CAS  PubMed  Google Scholar 

  59. Collins, R. L. Reimpressed selective breeding for lateralization of handedness in mice. Brain Res. 564, 194–202 (1991).

    CAS  PubMed  Google Scholar 

  60. Cabib, S. et al. Paw preference and brain dopamine asymmetries. Neuroscience 64, 427–432 (1995).

    CAS  PubMed  Google Scholar 

  61. Barneoud, P., le Moal, M. & Neveu, P. J. Asymmetric distribution of brain monoamines in left- and right-handed mice. Brain Res. 520, 317–321 (1990).

    CAS  PubMed  Google Scholar 

  62. Barneoud, P. & Van der Loos, H. Direction of handedness linked to hereditary asymmetry of a sensory system. Proc. Natl Acad. Sci. USA 90, 3246–3250 (1993).

    CAS  PubMed  Google Scholar 

  63. Riddle, D. R. & Purves, D. Individual variation and lateral asymmetry of the rat primary somatosensory cortex. J. Neurosci. 15, 4184–4195 (1995).

    CAS  PubMed  Google Scholar 

  64. Chen-Bee, C. H. & Frostig, R. D. Variability and interhemispheric asymmetry of single-whisker functional representations in rat barrel cortex. J. Neurophysiol. 76, 884–894 (1996).

    CAS  PubMed  Google Scholar 

  65. Halpern, M. E., Gunturkun, O., Hopkins, W. D. & Rogers, L. J. Lateralization of the vertebrate brain: taking the side of model systems. J. Neurosci. 25, 10351–10357 (2005). Summary of recent studies of vertebrate brain asymmetries, particularly brain asymmetries in zebrafish and chicks.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hill, R. S. & Walsh, C. A. Molecular insights into human brain evolution. Nature 437, 64–67 (2005).

    CAS  PubMed  Google Scholar 

  67. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005). Accomplished the initial sequencing of the chimpanzee genome. This work will have a considerable impact on our understanding of the genomic regulation of human evolution.

  68. Khaitovich, P. et al. Parallel patterns of evolution in the genomes and transcriptomes of humans and chimpanzees. Science 309, 1850–1854 (2005).

    CAS  PubMed  Google Scholar 

  69. Preuss, T. M., Caceres, M., Oldham, M. C. & Geschwind, D. H. Human brain evolution: insights from microarrays. Nature Rev. Genet. 5, 850–860 (2004).

    CAS  PubMed  Google Scholar 

  70. Hobert, O., Johnston, R. J. Jr & Chang, S. Left-right asymmetry in the nervous system: the Caenorhabditis elegans model. Nature Rev. Neurosci. 3, 629–640 (2002). Overview of the molecular mechanisms that regulate asymmetries in the Caenorhabditis elegans nervous system.

    CAS  Google Scholar 

  71. Concha, M. L. & Wilson, S. W. Asymmetry in the epithalamus of vertebrates. J. Anat. 199, 63–84 (2001).

    CAS  PubMed  Google Scholar 

  72. Halpern, M. E., Liang, J. O. & Gamse, J. T. Leaning to the left: laterality in the zebrafish forebrain. Trends Neurosci. 26, 308–313 (2003).

    CAS  PubMed  Google Scholar 

  73. Kennedy, D. N. et al. Structural and functional brain asymmetries in human situs inversus totalis. Neurology 53, 1260–1265 (1999).

    CAS  PubMed  Google Scholar 

  74. Tanaka, S., Kanzaki, R., Yoshibayashi, M., Kamiya, T. & Sugishita, M. Dichotic listening in patients with situs inversus: brain asymmetry and situs asymmetry. Neuropsychologia 37, 869–874 (1999).

    CAS  PubMed  Google Scholar 

  75. Carlen, B. & Stenram, U. Primary ciliary dyskinesia: a review. Ultrastruct. Pathol. 29, 217–220 (2005).

    PubMed  Google Scholar 

  76. McManus, I. C., Martin, N., Stubbings, G. F., Chung, E. M. & Mitchison, H. M. Handedness and situs inversus in primary ciliary dyskinesia. Proc. Biol. Sci. 271, 2579–2582 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. McManus, C. Reversed bodies, reversed brains, and (some) reversed behaviors: of zebrafish and men. Dev. Cell 8, 796–797 (2005).

    CAS  PubMed  Google Scholar 

  78. Sun, T. et al. Early asymmetry of gene transcription in embryonic human left and right cerebral cortex. Science 308, 1794–1798 (2005). Measured differential gene expression levels in the Sylvian fissures between the left and right human fetal brains and identified 27 asymmetrically expressed genes using SAGE, real-time reverse transcription (RT)-PCR and in situ hybridization.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Palmer, A. R. Symmetry breaking and the evolution of development. Science 306, 828–833 (2004).

    CAS  Google Scholar 

  80. Tanabe, Y. & Jessell, T. M. Diversity and pattern in the developing spinal cord. Science 274, 1115–1123 (1996).

    CAS  PubMed  Google Scholar 

  81. Dodd, J., Jessell, T. M. & Placzek, M. The when and where of floor plate induction. Science 282, 1654–1657 (1998).

    CAS  PubMed  Google Scholar 

  82. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).

    CAS  PubMed  Google Scholar 

  83. Rubenstein, J. L., Shimamura, K., Martinez, S. & Puelles, L. Regionalization of the prosencephalic neural plate. Annu. Rev. Neurosci. 21, 445–477 (1998).

    CAS  PubMed  Google Scholar 

  84. Tannahill, D., Harris, L. W. & Keynes, R. Role of morphogens in brain growth. J. Neurobiol. 64, 367–375 (2005).

    CAS  PubMed  Google Scholar 

  85. Chizhikov, V. V. & Millen, K. J. Roof plate-dependent patterning of the vertebrate dorsal central nervous system. Dev. Biol. 277, 287–295 (2005).

    CAS  PubMed  Google Scholar 

  86. Fukuchi-Shimogori, T. & Grove, E. A. Neocortex patterning by the secreted signaling molecule FGF8. Science 294, 1071–1074 (2001).

    CAS  PubMed  Google Scholar 

  87. Herbert, M. R. et al. Brain asymmetries in autism and developmental language disorder: a nested whole-brain analysis. Brain 128, 213–226 (2005).

    CAS  PubMed  Google Scholar 

  88. Hugdahl, K. et al. Central auditory processing, MRI morphometry and brain laterality: applications to dyslexia. Scand. Audiol. Suppl. 49, 26–34 (1998).

    CAS  PubMed  Google Scholar 

  89. Galaburda, A. M., Menard, M. T. & Rosen, G. D. Evidence for aberrant auditory anatomy in developmental dyslexia. Proc. Natl Acad. Sci. USA 91, 8010–8013 (1994).

    CAS  PubMed  Google Scholar 

  90. Falkai, P. et al. Loss of Sylvian fissure asymmetry in schizophrenia. A quantitative post mortem study. Schizophr. Res. 7, 23–32 (1992).

    CAS  PubMed  Google Scholar 

  91. Pascual-Castroviejo, I., Pascual-Pascual, S. I., Viano, J., Martinez, V. & Palencia, R. Unilateral polymicrogyria: a common cause of hemiplegia of prenatal origin. Brain Dev. 23, 216–222 (2001).

    CAS  PubMed  Google Scholar 

  92. Chang, B. S. et al. A familial syndrome of unilateral polymicrogyria affecting the right hemisphere. Neurology 66, 133–135 (2006).

    CAS  PubMed  Google Scholar 

  93. Annett, M. Handedness and cerebral dominance: the right shift theory. J. Neuropsychiatry Clin. Neurosci. 10, 459–469 (1998).

    CAS  PubMed  Google Scholar 

  94. Wright, C. V. Mechanisms of left–right asymmetry: what's right and what's left? Dev. Cell 1, 179–186 (2001).

    CAS  PubMed  Google Scholar 

  95. Levin, M. Left–right asymmetry in embryonic development: a comprehensive review. Mech. Dev. 122, 3–25 (2005). Gives a comprehensive summary of asymmetries in invertebrates and vertebrates and discusses molecular mechanisms that lead to these asymmetries.

    CAS  PubMed  Google Scholar 

  96. Capdevila, J., Vogan, K. J., Tabin, C. J. & Izpisua Belmonte, J. C. Mechanisms of left–right determination in vertebrates. Cell 101, 9–21 (2000).

    CAS  PubMed  Google Scholar 

  97. Hamada, H., Meno, C., Watanabe, D. & Saijoh, Y. Establishment of vertebrate left–right asymmetry. Nature Rev. Genet. 3, 103–113 (2002).

    CAS  PubMed  Google Scholar 

  98. Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M. & Tabin, C. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82, 803–814 (1995).

    CAS  PubMed  Google Scholar 

  99. Rodriguez Esteban, C. et al. The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature 401, 243–251 (1999).

    CAS  PubMed  Google Scholar 

  100. Boettger, T., Wittler, L. & Kessel, M. FGF8 functions in the specification of the right body side of the chick. Curr. Biol. 9, 277–280 (1999).

    CAS  PubMed  Google Scholar 

  101. Nonaka, S., Shiratori, H., Saijoh, Y. & Hamada, H. Determination of left–right patterning of the mouse embryo by artificial nodal flow. Nature 418, 96–99 (2002).

    CAS  PubMed  Google Scholar 

  102. McGrath, J., Somlo, S., Makova, S., Tian, X. & Brueckner, M. Two populations of node monocilia initiate left–right asymmetry in the mouse. Cell 114, 61–73 (2003).

    CAS  PubMed  Google Scholar 

  103. Nonaka, S. et al. Randomization of left–right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95, 829–837 (1998).

    CAS  PubMed  Google Scholar 

  104. Levin, M., Thorlin, T., Robinson, K. R., Nogi, T. & Mercola, M. Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left–right patterning. Cell 111, 77–89 (2002).

    CAS  PubMed  Google Scholar 

  105. Fukumoto, T., Blakely, R. & Levin, M. Serotonin transporter function is an early step in left–right patterning in chick and frog embryos. Dev. Neurosci. 27, 349–363 (2005).

    CAS  PubMed  Google Scholar 

  106. Fukumoto, T., Kema, I. P. & Levin, M. Serotonin signaling is a very early step in patterning of the left–right axis in chick and frog embryos. Curr. Biol. 15, 794–803 (2005). References 96–106 are excellent studies of molecular regulation of body asymmetries.

    CAS  PubMed  Google Scholar 

  107. Harris, J. A., Guglielmotti, V. & Bentivoglio, M. Diencephalic asymmetries. Neurosci. Biobehav. Rev. 20, 637–643 (1996).

    CAS  PubMed  Google Scholar 

  108. Concha, M. L., Burdine, R. D., Russell, C., Schier, A. F. & Wilson, S. W. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28, 399–409 (2000).

    CAS  PubMed  Google Scholar 

  109. Bisgrove, B. W., Essner, J. J. & Yost, H. J. Multiple pathways in the midline regulate concordant brain, heart and gut left–right asymmetry. Development 127, 3567–3579 (2000).

    CAS  PubMed  Google Scholar 

  110. Essner, J. J., Branford, W. W., Zhang, J. & Yost, H. J. Mesendoderm and left–right brain, heart and gut development are differentially regulated by pitx2 isoforms. Development 127, 1081–1093 (2000).

    CAS  PubMed  Google Scholar 

  111. Barth, K. A. et al. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy, and a subset of behavioral responses. Curr. Biol. 15, 844–850 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Owing to space limitations, we apologize for being unable to cite many excellent papers in this field. We thank the referees for critical reading and useful comments, and B. Chang for the MRI images in figure 4. The authors were supported by grants from the National Institute of Neurological Disorders and Stroke, National Institutes of Health. C.A.W. is an investigator of the Howard Hughes Medical Institute.

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Glossary

Protomap model

Proposed by Pasko Rakic. He suggested that regionalization is mainly controlled by molecular determinants that are intrinsic to the proliferative zone of the neocortex. The 'proliferative units' in the ventricular zone form a protomap of prospective cortical regions. Postmitotic neurons migrating from the ventricular zone maintain the regional properties of the proliferative units.

Protocortex model

Proposed by Dennis O'Leary. He suggested that regionalization is controlled in large part by extrinsic influences, such as thalamocortical inputs.

Sylvian fissures

The deepest and most prominent of the cortical fissures (clefts). They separate the frontal lobes and temporal lobes in both hemispheres.

Broca's area

The left inferior frontal gyrus of the frontal lobe of the human cortex. This area is responsible for speech and for understanding language. Injuries to this area can cause Broca's aphasia, which is characterized by non-fluent speech, few words, short sentences and many pauses. Patients normally lose the ability to understand or produce grammatically complex sentences.

Wernicke's area

The left posterior section of the superior temporal gyrus, where the temporal lobe and parietal lobe meet. It is involved in the comprehension of written or spoken language. People with damage in this area speak fluently, but often using words or jumbled syllables that make no sense; this is known as Wernicke's aphasia.

Magnetic source imaging

The detection of the changing magnetic fields that are associated with brain activity and their subsequent overlaying on magnetic resonance images to identify the precise source of the signal.

Paw preference

In a food-reaching task, paw preference measures the frequency of using either the left or the right front paw to reach food. It has been observed in mice, rats, cats and dogs.

Serial analysis of gene expression

(SAGE). A method for comprehensive analysis of gene expression levels and patterns using PCR amplification and generating SAGE libraries.

Notochord

A structure composed of cells derived from the mesoderm and defines the primitive axis of the embryo. It lies between the neural tube (spinal cord) and the gut.

Morphogen

A diffusible substance that carries information influencing the movement and organization of cells during morphogenesis. It normally forms a concentration gradient.

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Sun, T., Walsh, C. Molecular approaches to brain asymmetry and handedness. Nat Rev Neurosci 7, 655–662 (2006). https://doi.org/10.1038/nrn1930

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