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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.

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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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