Molecular approaches to brain asymmetry and handedness

Abstract

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.